KR101538006B1 - Methods and compositions for reducing body fat and adipocytes - Google Patents

Abstract

Formula (I) and / or (V) compounds (X is a -OR _1, -SR _2, or _{-NR 3 R 4, R 1,} R 2, R 3, R 4, R 5, R 6, R a ₇ , R ₇ ', Z, Y, n, y and x are as defined herein, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, (E.g., topically) administering one or more compounds of one or more of the following: a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solubilized derivative or prodrug thereof.

Description

[0001] METHODS AND COMPOSITIONS FOR REDUCING BODY FAT AND ADIPOCYTES [0002]

                          Related application

This application claims the benefit of 35 U.S.C. U.S.S.N., filed July 13, 2012, in accordance with §120. 13 / 548,482 and 35 U.S.C. According to §119 (e), US Provisional Application No. U.S.S.N. 61 / 577,332, each of which is incorporated herein by reference in its entirety.

The present invention relates to methods and compositions for reducing fat and / or fat cells in the body of an individual. More specifically, body fat can be reduced by, for example and by way of non-limiting example, topical administration of a compound, including Tafluprost, to a subject, as described herein.

Excessive body fat is an important factor causing human illness, disability and cosmetic impairment. For most people, excessive body fat is also a factor that lowers social psychological stress and self-esteem.

Excess body fat may be dispersed or may be concentrated at a particular site (s) of the body. This may be accompanied by, for example, significant and inadequate fat accumulation in the abdomen, buttocks, chest, thighs, arms and / or jaws. In addition, this may involve, for example, excessive breast tissue in a woman or a male, i.e., a gynecomastia. Such local fat accumulation may be caused by constitutional factors, diseases, hormonal conditions or side effects of medication or other substances. Even if there is no disease, it is nevertheless a cosmetic reason for individuals who want to recognize and correct excess fat.

Many medical symptoms appear to be a factor of excessive body fat. Examples include, but are not limited to, drug-induced obesity, hypothyroidism, hypogonadal hypothyroidism, hypothalamic obesity, polycystic ovarian disease, depression, binge eating, Frederick-Willi Syndrome, Bardet-Biddle Syndrome, Cohen Syndrome, Down Syndrome, Turner syndrome, growth hormone deficiency, growth hormone resistance, and leptin deficiency or resistance. Excessive local fat accumulation that damages appearance, such as excessive posterior neck fat, may be associated with HIV lipodystrophy, Cushing's syndrome and Caustic-Cushing syndrome (i. E., Other symptoms due to excessive body fat characteristic syndromes and excessive endogenous or exogenous corticosteroid concentrations) Other acquired fatty dystrophy, family history of dyspepsia, lipomatosis and Madelung disease.

Drugs known to cause excessive body fat include cortisol and analogues, other corticosteroids, megace, sulfonylureas, antiretroviral agents, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, oral contraceptives , Insulin, risperidone, clozapine, and thiazolidinediones.

Changes in hormone status, including physiological changes, such as pregnancy or contraception, can result in excessive body fat formation in an individual. Smoking cessation usually increases body weight and causes excess body fat accumulation. Trauma can also help to build up excess body fat by fixing or not using extremities. Similar problems can occur, for example, in individuals who do not behave due to injury. Some tumors, such as lipomas and liposarcomas, characterize a collection of local adipocytes that can be treated by methods used to reduce body fat. The lipomatosis includes all conditions characterized by multiple lymphoma formation in the body, such as multiple lymphomatosis of family history, adiposis dolorosis (delcom disease), pelvic lipomatosis, and the like.

Even without a baseline pathogen, an individual can have cosmetic anxieties about local or dispersed body fat deposits. This may be due to constitutional or genetic factors, developmental factors, age, sex, diet, drinking, or other lifestyle factors. Objects in this situation generally want to reduce significant amounts of fat in the abdomen, chest, breast, buttocks, hips, thighs, legs, knees, arms, jaws, neck and / or face parts. In some cases, the fat is not really overdone, but it may be rearranged, such as orbital fat prolapse due to aging or fat agglomeration of the fat.

Many methods are being developed to reduce or eliminate excess body fat. These methods are classified as extraction, metabolism or adipolytic methods. An extraction method such as lipoplasty (e.g., liposuction) or local extraction is a method of physically removing fat from the area. This method is expensive and may involve scarring, postoperative anomalies or restoration, discomfort, infection and other side reactions.

In contrast to extraction methods, metabolic methods, including systemic drug therapy, nutritional supplementation, instrumentation and exercise or other physical treatment, may be used to modify the metabolism of an individual (e.g., calorie consumption, consumption Or both). The problem is that this method can not typically be performed only on specific parts of the body. Another problem is that water, carbohydrates, proteins, vitamins, minerals and other nutrients can be reduced at the same time. In addition, traditional diet medications may exhibit undesirable side effects, such as chest tremor, tremor, insomnia, and / or excitement, in an individual using an irritant as an appetite suppressant. Traditional metabolic methods, such as diet and exercise, are not applicable to anyone, despite their good health.

The method of fat dissolution is intended to cause degradation of adipocytes and / or fat-containing products. For example, fat accumulation can be reduced by exposure to cold or deoxycholate, a solubilizing agent that breaks down cell membranes and causes local necrosis. The problem with this method is that it is difficult to differentiate between adipose tissue and other adjacent tissues, the presence of barriers that require the use of hypodermic needles or special devices for the delivery of these agents, and possible side effects such as necrosis, inflammation and pain.

Accordingly, there is a need for a new composition and local administration method for reducing fat in the body of an individual.

The present invention is based on the discovery that tafloprost is more effective for topical administration for body fat reduction than bimatoprost. Tatoflurost analogues such as esters, thioesters, amides and free acids of tatofurost are also expected to be more effective for topical administration for body fat reduction than bimatoprost.

Thus, in one aspect, the invention provides a pharmaceutical composition comprising a compound of formula ( I ), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof To a subject in need thereof, a method of reducing fat in a subject in need thereof,

Wherein X is < RTI ID = 0.0 >

-OR ₁ wherein R ₁ is selected from the group consisting of hydrogen, a hydroxy protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, Optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heteroaryl;

-SR ₂ wherein R ₂ is selected from the group consisting of hydrogen, a thiol protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, Aryl, optionally substituted heteroaryl; or

-NR ₃ R ₄ wherein R ₃ and R ₄ are independently selected from the group consisting of hydrogen, an amino protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, Substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R ₃ and R ₄ are connected to form an optionally substituted heterocyclyl ring.

In certain embodiments, when X is -OR < _{1 &} gt ;, for use in the present invention, the compound of formula ( II ), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, Isotopically enriched derivatives or prodrugs are provided:

In certain embodiments, R < ₁ > is hydrogen. In certain embodiments, R < _{1 >} is an oxygen protecting group. In certain embodiments, R < _{1 >} is an optionally substituted alkyl. In certain embodiments, R ₁ is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl, or sec-butyl. In certain embodiments, R ₁ is isopropyl (-CH (CH ₃ ) ₂ ).

In certain embodiments, when X is-SR ₂ , the compound of formula ( III ) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotope Concentrated derivatives or prodrugs are provided:

In certain embodiments, R < ₂ > is hydrogen. In certain embodiments, R ₂ is a thiol protecting group. In certain embodiments, R < _{2 >} is an optionally substituted alkyl. In certain embodiments, R ₂ is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl, or sec-butyl. In certain embodiments, R ₂ is isopropyl (-CH (CH ₃ ) ₂ ).

In certain embodiments, when X is -NR ₃ R ₄ , the compound of formula ( IV ) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, Prodrugs are provided:

In certain embodiments, R < ₃ > is hydrogen. In certain embodiments, R < ₃ > is a nitrogen protecting group. In certain embodiments, R < ₃ > is an optionally substituted alkyl. In certain embodiments, R ₃ is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In certain embodiments, R ₃ is isopropyl (-CH (CH ₃ ) ₂ ). In certain embodiments, R < ₄ > is hydrogen. In certain embodiments, R < ₄ > is a nitrogen protecting group. In certain embodiments, R < ₄ > is an optionally substituted alkyl. In certain embodiments, R ₃ and R ₄ are connected to form an optionally substituted heterocyclyl ring.

In certain embodiments, the compound of formula ( II ) wherein R ₁ is hydrogen is a compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof, It is also referred to herein as tafloprost free acid:

In certain embodiments, the compound of formula ( II ) wherein R ₁ is isopropyl is selected from the group consisting of the following compounds or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof , Which is also referred to herein as < RTI ID = 0.0 >

In another aspect, the formula (V) compound or a pharmaceutically acceptable thereof, pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, polymorphs, tautomers, isotopically enriched derivative or prodrug thereof, for example, alone or in formula (I a ) ≪ / RTI > in combination with a compound of formula < RTI ID = 0.0 &

Wherein R ₅ , R ₆ , R ₇ , R _{7 '} , Z, X, Y, n, y and x are as defined herein.

In certain embodiments, any of the above-described methods further comprises administering one or more additional compounds of Formula ( I ), ( II ), ( III ), ( IV ), and / or ( V ) Salts, hydrates, solvates, stereoisomers, polymorphs, tautomers, or isotopically enriched derivatives thereof.

In certain embodiments, the subject is selected from the group consisting of obesity, excessive breast fat, excessive jaw fat, gynecomastia, drug induced obesity, hypothyroidism, hypoparathyroidism, hypothalamic obesity, polycystic ovarian disease, depression, Growth Hormone Deficiency, Growth Hormone Deficiency, Leptin Deficiency or Tolerance, Cushing's Syndrome, Caustic Cushing's Syndrome, Posterior Cervical Syndrome, Cerebral Palsy Syndrome, Cerebral Palsy Syndrome, Of patients with acute pancreatitis or acute pancreatitis, such as acromegaly / posterior neck hyperplasia ("buffalo hump"), facial edema, HIV lipodystrophy, orbital fat prolapse, age-related descent of abnormal fat, , Lipomatosis, or madellon disease, or is likely to be sick. In certain embodiments, the subject is suffering from or susceptible to obesity, gynecomastia, HIV lipodystrophy, lipoma, or excessive fat symptoms of the jaw.

In certain embodiments, the route of administration is selected from the group consisting of topical, subcutaneous, intradermal, and intraluminal. In certain embodiments, the route of administration is topical. In certain embodiments, the site of administration is selected from the group consisting of skin, eyes, or mucosa. In certain embodiments, the route of administration is selected from the group consisting of subcutaneous, intradermal, and intralesional. In certain embodiments, the administration is in a body part selected from the group consisting of abdomen, chest, breast, buttocks, hips, thighs, legs, knees, arms, jaws, neck and face. In certain embodiments, topical administration is transdermal administration.

In another aspect there is provided a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula ( I ), ( II ), ( III ), ( IV ) and / or ( V ), or a pharmaceutically acceptable salt, hydrate, solvate, There is provided a pharmaceutical composition for reducing body fat, for example, comprising a stereoisomer, polymorph, tautomer or isotopically enriched derivative, and optionally one or more excipients. In certain embodiments, the composition is suitable for topical, subcutaneous, intradermal, or intra-site delivery. In certain embodiments, the composition comprises the compound of Formula ( I ), ( II ), ( III ), ( IV ) and / or ( V ) in a non-limiting example at a concentration of from about 0.01% to about 10% w / v). In certain embodiments, the excipient is Lipoderm ^® .

The foregoing aspects and implementations of the present invention will be more fully understood from the following detailed description, examples, and claims.

                            Justice

Chemical definition

Definitions for specific functional groups and chemical terms are described in more detail below. Chemical elements CAS version of ^{Handbook of Chemistry and Physics, 75 th} Ed. Are listed in accordance with the elements in the cover, and certain functional groups are generally defined as described therein. In addition, general rules and specific functionalities and reactivity with organic chemistry are described in Organic Chemistry , Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry , 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; And Carruthers, Some Modern Methods of Organic Synthesis , 3 ^rd Edition, Cambridge University Press, Cambridge, 1987.

Certain of the compounds described herein may contain one or more asymmetric centers and may exist in various isomeric forms, such as enantiomers and / or diastereomers. The compounds provided herein may be in the form of their respective enantiomers, diastereomers or geometric isomers, or they may be in the form of mixtures of enriched mixtures of one or more stereoisomers and stereoisomers, including racemic mixtures. In certain embodiments, the compound described herein is an enantiopure compound. In certain other embodiments, mixtures of stereoisomers are provided.

In addition, certain of the compounds described herein may have one or more double bonds, which may exist in either the cis or trans or E or Z isomers, unless otherwise stated. The present invention additionally encompasses individual isomers substantially free of other isomers, and as another example mixtures of various isomers, such as a racemic mixture of E / Z isomers or a mixture in which one E / Z isomer is enriched.

The terms "enantiomerically enriched "," enantiomerically pure "and" non-racemic "are used interchangeably herein, and the term" enantiomerically enriched " (E. G. Greater than 1: 1 by weight). ≪ / RTI > For example, formulations enriched in the enantiomeric aspect of the (S) -enantiomer are preferred because the (S) -enantiomer is more than 50 wt%, more preferably more than 75 wt% By weight, more preferably at least 80% by weight, based on the total weight of the composition. In some embodiments, the concentration is well over 90% by weight and provides "substantially enantiomerically pure" or "substantially non-racemic" , Which refers to a preparation having a composition wherein one enantiomer is at least 85 wt%, more preferably at least 90 wt%, and even more preferably at least 95 wt%, relative to the other enantiomers. In a preferred embodiment, the enriched enantiomerically enriched composition is more efficacious in terms of therapeutic utility per unit weight than such a racemic mixture of the composition. Enantiomers can be separated from the mixture by methods known to those skilled in the art, such as by chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or the desired enantiomers can be prepared via asymmetric synthesis have. For example, Jacques, et al., Enantiomers, Racemates and Resolution (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33: 2725 (1977); Eliel, EL Stereochemistry of Carbon compounds (McGraw-Hill, NY, 1962); And Wilen, SH Table of Resolving Agents and Optical Resolution p. 268 (EL Eliel, Ed., Univ. Of Notre Dame Press, Notre Dame, IN 1972).

When listing a range of values, it is intended to encompass each value and sub-range within the range. For example "C _1-6 alkyl" is _{C 1, C 2, C 3} , C 4, C 5, C 6, C 1-6, C 1-5, C 1-4, C 1-3, C 1- _{2, C 2- C 6, C} 2-5, C 2-4, C 2-3, C 3-6, C 3-5, C 3-4, C 4-6, C 4-5, and C _Is intended to encompass _5-6 alkyl.

As used herein, alone or as part of another group, "alkyl" refers to a radical of a straight chain or branched saturated hydrocarbon group of 1-20 carbon atoms ("C _1-20 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C _1-10 alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C _1-6 alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, the alkyl group has one carbon atom ("C ₁ alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C _2-6 alkyl"). Examples of the C _1-6 alkyl groups are methyl (C _1), ethyl (C _2), n- propyl (C _3), iso-propyl (C _3), n- butyl (C _4), tert- butyl (C ₄ ), sec- butyl (C _4), iso-butyl (C _4), n- pentyl (C _5), 3- fentanyl (C _5), amyl (C _5), neopentyl (C _5), 3- methyl Butanyl (C ₅ ), tertiary amyl (C ₅ ) and n-hexyl (C ₆ ). Unless otherwise indicated, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl"), or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C _1-6 alkyl (e.g., -CH ₃ ). In certain embodiments, the alkyl group is substituted C _1-6 alkyl.

As used herein, "perhaloalkyl" or "halo substituted alkyl" refers to alkyl having 1-10 carbon atoms as defined herein, wherein all hydrogen atoms are each independently halogen, road and refers to the group substituted alkyl ( "C _1-10 alkyl perhalo"). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms ("C _1-6 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 5 carbon atoms ("C _1-5 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms ("C _1-4 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms ("C _1-3 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms ("C _1-2 spiroalkyl"). In some embodiments, all hydrogen atoms are each substituted with fluoro. In some embodiments, all of the hydrogen atoms are each chloro substituted. Examples of perhaloalkyl groups include -CF ₃ , -CF ₂ CF ₃ , -CF ₂ CF ₂ CF ₃ , -CCl ₃ , -CFCl ₂ , -CF ₂ Cl, and the like.

As used herein, "alkyloxy" refers to an alkyl group defined herein wherein the point of attachment is oxygen and substituted with oxygen. In certain embodiments, the alkyl group has from 1 to 6 carbon atoms ("C _1-6 alkyloxy"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C _1-4 alkyloxy"). Examples of the C _1-4 alkyloxy groups include methoxy (C _1), ethoxy (C _2), propoxy (C _3), isopropoxy (C _3), butoxy (C _4), tert - butoxycarbonyl (C ₅ ), and the like. Examples of the C _1-6 alkyloxy group include the above-mentioned C _1-4 alkyloxy groups and groups such as pentyloxy (C ₅ ), isopentyloxy (C ₅ ), neopentyloxy (C ₅ ), hexyloxy (C ₆ ) And the like. Unless otherwise indicated, each instance of an alkyl moiety of an alkyloxy group is independently either unsubstituted ("unsubstituted alkyloxy"), or substituted with one or more substituents ("substituted alkyloxy"). In certain embodiments, the alkyloxy group is unsubstituted C _1-6 alkyloxy. In certain embodiments, the alkyloxy group is substituted C _1-6 alkyloxy.

As used herein, "alkylcarboxy" refers to a group of formula -C (= O) OR ^{a wherein} R ^a is an alkyl group as defined herein. In certain embodiments, the alkyl of the alkyl carboxy group has from 1 to 6 carbon atoms ("C _1-6 alkyl carboxy"). In some embodiments, the alkyl of the alkyl carboxy group has from 1 to 5 carbon atoms ("C _1-5 alkyl carboxy"). In some embodiments, the alkyl of the alkyl carboxy group has from 1 to 4 carbon atoms ("C _1-4 alkyl carboxy"). In some embodiments, the alkyl of the alkyl carboxy group has from 1 to 3 carbon atoms ("C _1-3 alkyl carboxy"). In some embodiments, the alkyl of the alkyl carboxy group has 1 to 2 carbon atoms ("C _1-2 alkyl carboxy"). Unless otherwise indicated, alkyl of the alkylcarboxy group is independently in each instance independently unsubstituted ("unsubstituted alkylcarboxy"), or substituted with one or more substituents ("substituted alkylcarboxy"). In certain embodiments, the alkylcarboxy group is unsubstituted C _1-6 alkylcarboxy. In certain embodiments, the alkyl carboxy group is substituted C _1-6 alkyl carboxy.

Herein alone or as part of another group, "alkenyl", carbon-refers to a radical of the hydrocarbon group include a linear or branched, having a carbon number of 2-20 or more carbon-carbon double bond is one ( "C _2-20 Al Kenil "). In some embodiments, the alkenyl group has from 2 to 10 carbon atoms ("C _2-10 alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C _2-6 alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C _2-5 alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C _2-4 alkenyl"). In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C _2-3 alkenyl"). In some embodiments, the alkenyl group has 2 carbon atoms ( "C ₂ alkenyl"). One or more carbon-carbon double bonds may be internal (e.g., as in 2-butenyl), or may be terminal (e.g., as in 1-butenyl). Examples of the C _2-4 alkenyl group include ethynyl (C ₂ ), 1-propenyl (C ₃ ), 2-propenyl (C ₃ ), 1-butenyl (C ₄ ) C ₄ ), butadienyl (C ₄ ), and the like. Examples of the C _2-6 alkenyl group include the above-mentioned C _2-4 alkenyl group and pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. Unless otherwise indicated, each alkenyl group is independently either unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C _2-6 alkenyl. In certain embodiments, the alkenyl group is substituted C _2-6 alkenyl.

As used herein, alone or as part of another group, "alkynyl" refers to a radical of a straight or branched hydrocarbon group having from 2 to 20 carbon atoms in which the carbon-carbon triple bond is one or more ("C _2-20 alkynyl "). In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C _2-10 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C _2-6 alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C _2-5 alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C _2-4 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C _2-3 alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C ₂ alkynyl"). The at least one carbon-carbon triple bond may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). Examples of C _2-4 alkynyl groups include, but not limited, ethynyl (C _2), 1- propynyl (C _3), 2- propynyl (C _3), 1- butynyl (C _4), 2-butynyl, and the like (C _4). Examples of the C _2-6 alkenyl group include the aforementioned C _2-4 alkynyl group and pentynyl (C ₅ ), hexynyl (C ₆ ), and the like. Unless otherwise indicated, each of the alkynyl groups is independently unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents ("substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C _2-6 alkynyl. In certain embodiments, the alkynyl group is substituted C _2-6 alkynyl.

As used herein, "saturated or unsaturated acyclic hydrocarbons" refers to saturated or unsaturated, straight or branched hydrocarbon radicals having 1 to 20 carbon atoms, optionally having one or more carbon-carbon double bonds or triple bonds, Quot; In certain embodiments, the hydrocarbon group is saturated. In some embodiments, the hydrocarbon group is unsaturated and has at least one carbon-carbon double bond or triple bond. In some embodiments, the hydrocarbon group contains 1-10 carbon atoms. In certain embodiments, the hydrocarbon group comprises 1-5 carbon atoms. In some embodiments, the hydrocarbon group contains 1-4 carbon atoms. In some embodiments, the hydrocarbon group comprises 1-3 carbon atoms. In some embodiments, the hydrocarbon group comprises 1 to 2 carbon atoms.

As used herein, "carbocyclyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having 3-7 ring carbons and zero heteroatoms in the non-aromatic ring system ("C _3-7 carbocyclyl" ). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C _3-6 carbocyclyl"). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C _3-6 carbocyclyl"). Exemplary C _3-7 carbocyclyl groups include but are not limited to cyclopropyl (C ₃ ), cyclopropenyl (C ₃ ), cyclobutyl (C ₄ ), cyclobutenyl (C ₄ ), cyclopentyl C _5), cyclopentenyl (C _5), cyclohexyl (C _6), cyclohexenyl (C _6), cyclohexanone dienyl (C _6), cycloheptyl (C _7), cycloheptane-butenyl (C ₇₎ , Cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), and the like. As described in the foregoing examples, in certain embodiments, the carbocyclyl group may be fused with a monocyclic ("monocyclic carbocyclyl") or polycyclic (eg, bicyclic system ("bicyclic carbocyclyl"), Linked or spiro ring system), which may contain one or more carbon-carbon double bonds or triple bonds, or may be saturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring is fused with one or more aryl or heteroaryl groups as defined above and the point of attachment is on the carbocyclyl ring, in which case, The carbon number is referred to as the carbon number in the carbocyclic ring system. Unless otherwise indicated, each of the carbocyclyl groups is independently unsubstituted ("unsubstituted carbocyclyl"), or substituted with 1, 2, 3, 4 or 5 substituents as described herein "Substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is unsubstituted C _3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C _3-10 carbocyclyl.

In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl group having 3 to 7 ring carbon atoms ("C _3-7 cycloalkyl"). In some embodiments, the cycloalkyl group has 3 to 6 ring carbon atoms ("C _3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has 5 to 6 ring carbon atoms ("C _5-6 cycloalkyl"). Examples of C _5-6 cycloalkyl groups include cyclopentyl (C ₅ ) and cyclohexyl (C ₅ ). Examples of C _3-6 cycloalkyl groups include C _5-6 cycloalkyl groups as described above, and cyclopropyl (C ₃ ) and cyclobutyl (C ₄ ). Examples of C _3-7 cycloalkyl groups include C _3-6 cycloalkyl groups as described above and cycloheptyl (C ₇ ). Unless otherwise indicated, each cycloalkyl group is independently either unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C _3-7 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C _3-7 cycloalkyl.

&Quot; Heterocyclyl ", as used herein alone or as part of another group, has from 1 to 4 heteroatoms with a ring carbon atom and the heteroatoms are each independently selected from N, O and S, Refers to the radical of a non-aromatic ring system ("3-8 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence is allowed. The heterocyclyl group may be monocyclic ("monocyclic heterocyclyl") or polycyclic (eg, fused, bridged or spiro ring system fused with a bicyclic system ("bicyclic heterocyclyl")), saturated , One or more carbon-carbon double bonds or triple bonds. Heterocyclyl dicyclic ring systems may include one or more heteroatoms in one or both rings. Also, "heterocyclyl" refers to a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups and the attachment point is on a carbocyclyl or heterocyclyl ring, or a ring system as defined above Wherein the heterocyclyl ring is fused with one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring, in which case the number of the members making up the ring is the number of rings in the heterocyclyl ring system Continued to the number of the member.

In some embodiments, the heterocyclyl group is a 5-8-membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from N, O and S (" 5-8 membered heterocyclyl "). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms and each heteroatom is independently selected from N, O, and S (" 5-6 membered heterocyclyl "). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from N, O, and S. In some embodiments, In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from N, O, and S. In some embodiments, In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from N, O, and S. In some embodiments, Examples of tertiary heterocyclyls containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, thienyl. Examples of quaternary heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl. Examples of five-membered heterocyclyls containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and Pyrrol-2,5-dione. Examples of five-membered heterocyclyls containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl and dithiolanyl. Examples of five-membered heterocyclyls containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl and thiadiazolinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazininyl. Examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl and thiepanyl. Examples of 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocannyl, oxecanyl and thiocanyl. Unless otherwise indicated, each heterocyclyl is independently unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is unsubstituted 3-8-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 8-membered heterocyclyl.

As used herein, alone or as part of another group, "aryl" refers to a monocyclic or polycyclic (e. G., Bicyclic or tricyclic) group having 4 to 10 ring carbon atoms and 0 heteroatoms in the aromatic ring system, Refers to the radical of a +2 aromatic ring system ("C _6-10 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C ₆ aryl "; e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C ₁₀ aryl"; eg, naphthyl, such as 1-naphthyl and 2-naphthyl). Also, "aryl" includes ring systems in which the aryl ring, as defined above, is fused with one or more cycloalkyl or heterocyclyl groups and wherein the attachment radical or point is on an aryl ring, Are assigned to the number of carbon atoms of the aryl ring system. Unless otherwise indicated, each of the aryl groups is independently unsubstituted ("unsubstituted aryl") or substituted with one or more substituents as described herein ("substituted aryl"). In certain embodiments, the aryl group is unsubstituted C _6-10 aryl. In certain embodiments, the aryl group is substituted C _6-10 aryl.

As used herein, either alone or as part of another group, "heteroaryl" refers to an aromatic ring system having 1-4 ring carbon atoms and each ring member is independently selected from N, O, Refers to a radical of a 5-14 membered monocyclic or polycyclic (e. G., Bicyclic) 4n + 2 aromatic ring system with a heteroatom ("5-10 membered heteroaryl"). In a heteroaryl group containing at least one nitrogen atom, the point of attachment may be a carbon or nitrogen atom since valence is allowed. Heteroaryl polycyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" means a ring system wherein a heteroaryl ring as defined herein is fused with one or more carbocyclyl or heterocyclyl groups and the point of attachment is on a heteroaryl ring, in which case the number of ring members Quot; is assigned to the number of the ring member in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused with one or more aryl groups and where the point of attachment is on an aryl or heteroaryl ring, (Aryl / heteroaryl) ring system in which the ring member is numbered. In a polycyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) in which one ring does not include a heteroatom, the point of attachment is either a ring, i.e., a ring that hinders the heteroatom ) Or on rings which do not include heteroatoms (e.g., 5-indolyl). In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having 1-4 ring heteroatoms provided to the aromatic ring system with ring carbon atoms, wherein each heteroatom is independently selected from N, O, and S. In some embodiments, ("5-10 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-8-membered aromatic ring system wherein each heteroatom is independently selected from N, O, and S, having 1-4 ring heteroatoms provided to the aromatic ring system and the ring carbon atom ("5-8 member heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having 1-4 ring heteroatoms provided to the aromatic ring system with ring carbon atoms, wherein each heteroatom is independently selected from N, O, and S. In some embodiments, ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from N, O, and S. In some embodiments, In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from N, O, and S. In some embodiments, the 5-6 membered heteroaryl has one ring heteroatom selected from N, O, and S. In certain embodiments, Examples of pentafluoroheteroaryl containing one heteroatom include, but are not limited to, pyrrolyl, furanyl and thiophenyl. Examples of five-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, isoxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Examples of five-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, thiadiazolyl. Examples of five-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl and pyrazinyl. Examples of six-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Examples of 7-membered heteroaryl containing one heteroatom include, but are not limited to, azetpinyl, oxepinyl and thiepinyl. Examples of 5,6-bicyclic heteroaryl include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisopyranyl, Benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiadiazolyl, indolizinyl and furunyl. The term " heteroaryl " Examples of 6,6-bicyclic heteroaryl include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl do. Unless otherwise indicated, each of the heteroaryl groups is independently unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is unsubstituted 5-10 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-10 membered heteroaryl.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl referred to without the suffix "-en " are each independently selected from alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, And as defined herein, a mono radical is bonded directly to the parent moiety or other group by one bond (e.g., a single bond or a double bond). The monoradical group may also be optionally substituted, as defined herein. The groups designated by the suffix "-en " such as alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylel, arylene and heteroarylene groups are each alkyl, alkenyl, alkynyl, carbocycle (As defined herein) refers to a diradical of a carbocycle, a carbocycle, a heterocycle, a heterocycle, a heterocycle, a heterocycle, a heterocycle, The parent molecule and other groups). In addition, the di radical may be optionally substituted.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted as defined herein (e.g., "substituted" or "unsubstituted" Substituted " or " unsubstituted "heterocyclyl," substituted " or " unsubstituted " carbocyclyl, Quot; or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted ", which is preceded or not by the term" optional ", means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is replaced by an acceptable substituent, Substituted, substituted or unsubstituted, to form a spontaneously converted compound, such as by an array, cyclization, elimination or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when two or more positions are substituted in a given structure, the substituents are the same or different at each position.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted as defined herein (e.g., "substituted" or "unsubstituted" Substituted " or " unsubstituted "heterocyclyl," substituted " or " unsubstituted " carbocyclyl, Quot; or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted ", which is preceded or not by the term" optional ", means that at least one hydrogen present on a group (e.g., carbon or nitrogen atom) is replaced by an acceptable substituent, Substituents which form a compound that undergoes spontaneous conversion, such as by sequencing, cyclization, elimination, or other reactions. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions (eg, 1, 2, 3, 4, or 5 places) of the group, and when two or more positions are substituted in a given structure, The substituents are the same or different at each position. The term " substituted "encompasses all permissible organic compound substituents, substitution with any of the substituents described herein to allow stable compounds to form. The present invention encompasses any and all such combinations to arrive at a stable compound. In the present invention, a heteroatom such as nitrogen may be any suitable substituent described herein, which satisfies the valence of a hydrophobic substituent and / or heteroatom and allows a stable moiety to be formed.

Examples of the carbon atom substituents, non-limiting example, a _{halogen, -CN, -NO 2, -N 3} , -SO 2 H, -SO 3 H, -OH, -OR aa, -ON (R bb) 2, _{^{-N (R bb) 2, -N}} (OR cc) R bb, -SH, -SR aa, -SSR cc, -C (= O) R aa, -CO 2 H, -CHO, -C (OR cc ^{_{) 2, -CO 2 R aa,}} -OC (= O) R aa, -OCO 2 R aa, -C (= O) N (R bb) 2, -OC (= O) N (R bb) 2, ^{-NR bb C (= O) R} aa, -NR bb CO 2 R aa, -NR bb C (= O) N (R bb) 2, -C (= NR bb) R aa, -C (= NR bb ^{) OR aa, -OC (= NR} bb) R aa, -OC (= NR bb) OR aa, -C (= NR bb) N (R bb) 2, -OC (= NR bb) N (R bb) ^{_{2, -NR bb C (= NR}} bb) N (R bb) 2, -C (= O) NR bb SO 2 R aa, -NR bb SO 2 R aa, -SO 2 N (R bb) 2, - ^{_{SO 2 R aa, -SO 2 OR}} aa, -OSO 2 R aa, -S (= O) R aa, -OS (= O) R aa, -Si (R aa) 3, -OSi (R aa) 3 -C (= S) N (R bb) 2, -C (= O) SR aa, -C (= S) SR aa, -SC (= S) SR aa, -SC (= O) SR aa, - ^{SC (= O) OR aa,} -OC (= O) SR aa, -SC (= O) R aa, -P (= O) 2 R aa, -OP (= O) 2 R aa, -P (= _{^{O) (R aa) 2,}} -OP (= O) (R aa) 2, -OP (= O) (OR cc) 2, -P (= O) 2 N (R bb) 2, -OP (= ^{_{O) 2 N (R bb)}} 2, -P (= O) (NR bb) 2, -OP (= O) (NR bb) 2, -NR bb P (= _{^{O) (OR cc) 2,}} -NR bb P (= O) (NR bb) 2, -P (R cc) 2, -P (R cc) 3, -OP (R cc) 2, -OP (R ^{_{cc) 3, -B (R aa}} ) 2, -B (OR cc) 2, -BR aa (OR cc), C 1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{3 -7} carbocyclyl, 3-8 immunogenic heterocyclyl, C _6-10 aryl, and 5-10 includes a bimodal heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, Aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4, or 5 R ^{d d} groups;

Or two hydrogen bonds to a single atom on the carbon atom to the group = O, = S, = NN (R bb) 2, = NNR bb C (= O) R aa, = NNR bb C (= O) OR aa , = NNR ^bb S (= O) ₂ R ^aa , = NR ^bb , or = NOR ^cc ;

Each R ^aa is independently selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, 3-8 membered heterocyclyl, C _6-10 aryl And 5-10 membered heteroaryl, or two R ^aa groups are connected to form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, Carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^{d d} groups;

Each R ^bb are, independently, ^{hydrogen, -OH, -OR aa, -N (} R cc) 2, -CN, -C (= O) R aa, -C (= O) N (R cc) 2 _{^{, -CO 2 R aa, -SO 2}} R aa, -C (= NR cc) OR aa, -C (= NR cc) N (R cc) 2, -SO 2 N (R cc) 2, -SO 2 _{^{R cc, -SO 2 OR cc,}} -SOR aa, -C (= S) N (R cc) 2, -C (= O) SR cc, -C (= S) SR cc, -P (= O) ^{_{2 R aa, -P (= O}} ) (R aa) 2, -P (= O) 2 N (R cc) 2, -P (= O) (NR cc) 2, C 1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, 3-8 immunogenic heterocyclyl, C _6-10 aryl and 5 to 10 bimodal or heteroaryl, R ^bb group two are connected Alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of hydrogen, 2, 3, 4 or 5 R ^{d d} groups;

Each R ^cc is, independently, hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, 3-8 immunogenic heterocyclyl, C _{6- 10} aryl and 5-10 membered heteroaryl, or two R ^cc groups are connected to form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkenyl, N, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups;

Each R ^dd is, independently, _{halogen, -CN, -NO 2, -N 3} , -SO 2 H, -SO 3 H, -OH, -OR ee, -ON (R ff) 2, -N ( _{^{R ff) 2, -N (OR}} ee) R ff, -SH, -SR ee, -SSR ee, -C (= O) R ee, -CO 2 H, -C (= O) OR ee, -OC ^{(= O) R ee, -OC} (= O) OR ee, -C (= O) N (R ff) 2, -OC (= O) N (R ff) 2, -NR ff C (= O) _{^{R ee, -NR ff CO 2 R}} ee, -NR ff C (= O) N (R ff) 2, -C (= NR ff) OR ee, -OC (= NR ff) R ee, -OC (= ^{NR ff) OR ee, -C (} = NR ff) N (R ff) 2, -OC (= NR ff) N (R ff) 2, -NR ff C (= NR ff) N (R ff) 2, _{^{-NR ff SO 2 R ee, -SO}} 2 N (R ff) 2, -SO 2 R ee, -SO 2 OR ee, -OSO 2 R ee, -S (= O) R ee, -Si (R ee ^{_{) 3, -OSi (R ee)}} 3, -C (= S) N (R ff) 2, -C (= O) SR ee, -C (= S) SR ee, -SC (= S) SR ee _{, -P (= O) 2 R} ee, -P (= O) (R ee) 2, -OP (= O) (R ee) 2, -OP (= O) (OR ee) 2, C 1- C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl, wherein Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, And heteroaryl is independently form a 0,1, 2, 3, 4, or is substituted with five R ^gg groups, or two R ^dd substituents bonded to two single atoms are connected to = O or = S and ;

Each R ^ee is independently selected from the group consisting of C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, 3-8 membered heterocyclyl, C _6-10 aryl And 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently selected from 0, 1, 2, 3, 4 or 5 ^Rgg ≪ / RTI >

Each R ^ff are, independently, hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, 3-8 immunogenic heterocyclyl, C _{6- 10} aryl and 5-10 membered heteroaryl, or two R ^ff groups are connected to form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkenyl, Aryl, and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups;

Each of R ^gg is, independently, _{halogen, -CN, -NO 2, -N 3} , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON (C _1-6 alkyl ) _2, -N (C _1-6 alkyl) _2, -N (OC _1-6 alkyl) (C _1-6 alkyl), -N (OH) (C 1-6 alkyl), -NH (OH), -SH, -SC _1-6 alkyl, -SS (C _1-6 alkyl), -C (= O) ( C 1-6 _{alkyl), -CO 2 H, -CO 2} (C 1-6 alkyl), -OC (= O) (C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C (= O) NH 2, -C (= O) N (C 1-6 alkyl) _2, -OC (= O) NH (C 1-6 alkyl), -NHC (= O) ( C 1-6 alkyl), -N (C _1-6 alkyl) C (= O) (C 1-6 alkyl) , -NHCO ₂ (C _1-6 alkyl), -NHC (= O) N (C 1-6 _{alkyl) 2, -NHC (= O)} NH (C 1-6 alkyl), -NHC (= O) NH _{2, -C (= NH) O} (C 1-6 alkyl), - OC (= NH) (C 1-6 alkyl), -OC (= NH) OC 1-6 alkyl, -C (= NH) N (C _{1-6 alkyl) 2, -C (= NH)} NH (C 1-6 alkyl), -C (= NH) NH 2, -OC (= NH) N (C 1-6 alkyl) _2, - OC (NH) NH (C _{1-6 alkyl), -OC (NH) NH 2} , -NHC (NH) N (C 1-6 _{alkyl) 2, -NHC (= NH)} NH 2, -NHSO 2 (C _1-6 alkyl), -SO ₂ N (C _{1-6 alkyl) 2, -SO 2 NH (C} 1-6 _{alkyl), -SO 2 NH 2, -SO} 2 C 1-6 alkyl, -SO ₂ OC _1-6 alkyl, -OSO ₂ C _1-6 alkyl, -SOC _1-6 alkyl, -Si (C _1-6 alkyl) _3, -OSi (C _{1-6 alkyl) 3 -C (= S) N} (C 1-6 _{alkyl) 2, C (= S)} NH (C 1-6 alkyl), C (= S) NH 2, -C (= O) S (C 1-6 alkyl), -C (= S) SC 1-6 alkyl, -SC (= S) SC _{1-6 alkyl, -P (= O) 2 (} C 1- ₆ alkyl), -P (= O) ( C 1-6 _{alkyl) 2, -OP (= O)} (C 1-6 _{alkyl) 2, -OP (= O)} (OC 1-6 alkyl) _2, C C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl ; Or two R ^gg substituents attached to one atom may be joined to form = O or = S.

The nitrogen atom may be unsubstituted or substituted as far as the valence permits, and includes primary, secondary, tertiary or quaternary nitrogen atoms. Examples of nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ^aa , -N (R ^cc ) ₂ , -CN, -C (= O) R ^aa , -C _{^{cc) 2, -CO 2 R aa}} , -SO 2 R aa, -C (= NR bb) R aa, -C (= NR cc) OR aa, -C (= NR cc) N (R cc) 2, _{^{-SO 2 N (R cc) 2}} , -SO 2 R cc, -SO 2 OR cc, -SOR aa, -C (= S) N (R cc) 2, -C (= O) SR cc, -C ^{(= S) SR cc, -P} (= O) 2 R aa, -P (= O) (R aa) 2, -P (= O) 2 N (R cc) 2, -P (= O) ( NR ^cc ) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-7 carbocyclyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 Or two R ^cc groups attached to the N atom are linked to form a 3-8 membered heterocyclyl or a 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl , Carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups, wherein R ^aa , R ^bb , R ^cc and R ^dd are independently selected from the group consisting of Respectively.

As used herein, the term "hydroxyl" or "hydroxy" refers to a group -OH. When expanded, the term "substituted hydroxyl" or "hydroxy-substituted" include, for other groups, such than an oxygen atom is hydrogen ^{-OR aa, -ON (R bb)} 2, -OC (= O) R aa ^{, -OC (= O) SR aa} , -OCO 2 R aa, -OC (= O) N (R bb) 2, -OC (= NR bb) R aa, -OC (= NR bb) OR aa, - ^{OC (= NR bb) N (} R bb) 2, -OS (= O) R aa, -OSO 2 R aa, -OSi (R aa) 3, -OP (R cc) 2, -OP (R cc) _{3, -OP (= O) 2} R aa, -OP (= O) (R aa) 2, -OP (= O) (OR cc) 2, -OP (= O) 2 N (R bb) 2, And -OP (= O) (NR ^bb ) ₂ , wherein R ^aa , R ^bb , and R ^cc are defined as defined herein.

As used herein, the term "thiol" or "thio" refers to a group -SH. When expanded, the term "substituted thiol" or "substituted alkylthio" is a thiol and refers to the group substituted by a group other than the sulfur atom is ^{hydrogen, -SR aa, -S = SR cc} , -SC (= S) SR aa, -SC ( = O) SR ^aa , -SC (= O) OR ^aa , and -SC (= O) R ^aa , wherein R ^aa and R ^cc are defined as defined herein.

As used herein, the term "amino" refers to the group -NH ₂ .

As used herein, the term "substituted amino" refers to an amino group, as defined herein, that is substituted once, twice, or three times.

The term "monosubstituted amino" as used herein refers to an amino group substituted with one group other than hydrogen, and includes -NH ( ^Rbb ), -NHC (= O) R ^aa , -NHCO ₂ R ^aa , -NHC ^{= O) N (R bb)} 2, -NHC (= NR bb) N (R bb) 2, -NHSO 2 R aa, -NHP (= O) (OR cc) 2, and -NHP (= O) ( NR ^bb) comprising a group selected from _2, in which R ^aa, R ^bb and R ^cc is defined as defined herein, R ^bb of -NH (R ^bb) group is not hydrogen.

As used herein, the term "twice-substituted amino" and refers to the group the other two groups substituted amino other than _{^{hydrogen, -N (R bb) 2,}} -NR bb C (= O) R aa, -NR bb CO 2 ^{R aa, -NR bb C (=} O) N (R bb) 2, -NR bb C (= NR bb) N (R bb) 2, -NR bb SO 2 R aa, -NR bb P (= O) (OR ^cc ) ₂ , and -NR ^bb P (= O) (NR ^bb ) ₂ , wherein R ^aa , R ^bb and R ^cc are defined as hereinbefore defined, The nitrogen atom directly bonded to the molecule is not substituted with hydrogen.

As used herein, the term "sulfonyl" is _{-S (= O) 2 OH,} -S (= O) 2 N (R bb) 2, -S (= O) 2 R aa, and -S (= O) ₂ OR ^aa , wherein R ^aa and R ^bb are defined as defined herein.

As used herein, the term "sulfinyl" refers to -S (= O) OH and -S (= O) R ^aa , wherein R ^aa is defined as herein.

As used herein, the term "carbonyl" is a direct bond to the parent molecule sp ² carbon hydride is O, N or S of atoms, and refers to the group, for example, these groups are a ketone (-C (= O) R ^aa ), carboxylic acid (-CO ₂ H), aldehyde (-CHO), ester _{^{(-CO 2 R aa, -C (}} = O) SR aa, -C (= S) SR aa), amide (-C ( ^{= O) N (R bb)} 2, -C (= O) NR bb SO 2 R aa, -C (= S) N (R bb) 2), and migration ^{(-C (= NR bb) R} aa, - (= NR ^bb ) OR ^aa ), -C (= NR ^bb ) N (R ^bb ) ₂ where R ^aa and R ^bb are defined as defined herein.

As used herein, the term "silyl " refers to the group -Si (R ^aa ) ₃ , wherein R ^aa is defined as herein.

As used herein, the term "carbonyl borough" is boranes, boronic acids, boronic esters, and borin borin acid esters, such as formula _{^{-B (R aa) 2, -B}} (OR cc) 2, and -BR ^aa (OR ^cc) Refers to boronyl groups wherein R ^aa and R ^cc are defined as hereinbefore defined.

As used herein, the term "phosphino" refers to the group -P (R ^cc ) ₃ , wherein R ^cc is defined as herein. An example of a phosphino group is triphenylphosphine.

Refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I) .

As used herein, "nitro" refers to the group -NO ₂ .

As used herein, "cyano" refers to a group -CN.

In the present application, "azido" refers to a group -N ₃ .

As used herein, "oxo" refers to the group = O.

Nitrogen atoms may be substituted or unsubstituted as valence permissible and include primary, secondary, tertiary or quaternary nitrogen atoms. Examples of nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR ^aa , -N (R ^cc ) ₂ , -CN, -C (= O) R ^aa , -C _{^{cc) 2, -CO 2 R aa}} , -SO 2 R aa, -C (= NR bb) R aa, -C (= NR cc) OR aa, -C (= NR cc) N (R cc) 2, _{^{-SO 2 N (R cc) 2}} , -SO 2 R cc, -SO 2 OR cc, -SOR aa, -C (= S) N (R cc) 2, -C (= O) SR cc, -C ^{(= S) SR cc, -P} (= O) 2 R aa, -P (= O) (R aa) 2, -P (= O) 2 N (R cc) 2, -P (= O) ( NR ^cc ) ₂ , C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C Two R ^cc groups, including _6-14 aryl and 5-14 membered heteroaryl, or two R ^cc groups bonded to the N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups and R ^aa , R ^bb , R ^cc and R < ^dd > Respectively.

In certain embodiments, the substituent present on the nitrogen atom is an "amino protecting group." Amino protecting groups, non-limiting ^{examples, -OH, -OR aa, -N (} R cc) 2, -C (= O) R aa, -C (= O) N (R cc) 2, -CO 2 R _{^{aa, -SO 2 R aa, -C}} (= NR cc) R aa, -C (= NR cc) OR aa, -C (= NR cc) N (R cc) 2, -SO 2 N (R cc) ^{_{2, -SO 2 R cc, -SO}} 2 OR cc, -SOR aa, -C (= S) N (R cc) 2, -C (= O) SR cc, -C (= S) SR cc, C _1-10 alkyl (for example, aralkyl, heteroaryl, aralkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 immunogenic heterocyclyl, C _6-14 aryl Alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl are independently selected from the group consisting of 0, 1, 2, 3, 4 Or 5 R ^{d d} groups, and R ^aa , R ^bb , R ^cc and R ^dd are defined as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting groups in Organic Synthesis , TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, do.

For example, an amino protecting group such as an amide group (e.g., Examples of the -C ( ^═O ) R ^aa include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, picolinic amide, 3-pyridyl-carboxamide, N - benzoyl phenyl alanyl derivative, benzamide, p - phenyl-benzamide, o - nitrophenyl O theta imide, o- nitrophenoxy cyano theta imide, theta acetonitrile Oh imide, (N'- dithio-benzyloxycarbonylamino) Oh theta imide, 3- (p - hydroxyphenyl) propanamide, 3- (o - nitrophenyl) propanamide, 2-methyl -2- (o - nitrophenoxy ( O -phenylazophenoxy) propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o -nitrocinnamide, N -acetylmethionine derivative , o- nitrobenzamide and o- (benzoyloxymethyl) benzamide.

Examples of amino protecting groups such as carbamate groups (e.g., -C (= O) OR ^aa ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- -Sulfo) fluorenylmethyl carbamate, 9- (2,7-dibromo) fluoroenyl methyl carbamate, 2,7-di- t -butyl- [9- (10,10- (10), 10,10,10-tetrahydrothiozantyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenylacyl carbamate (pheno c), 2,2,2- trichloroethyl carbamate , 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1,1- halo-ethyl carbamate, 1,1-dimethyl-2,2-di-bromoethyl-carbamate (DB- t -BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), (3,5-di- t -butylphenyl) -1-methylethylcarbamate ( t- Bumeoc), 2- ( 2'- And 4'-pyridyl) ethyl carbamate (Pyoc), 2- ( N, N -dicyclohexylcarboxamido) ethyl carbamate, t -butyl carbamate (BOC), 1- adamantyl carbamate Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamic carbamate (Coc), 4-nitrocinnamic mill carbamate (Noc) quinolyl carbamate, N - hydroxy-piperidinyl carbamates, alkyl dithiocarbamate, benzyl carbamate (Cbz), p - methoxybenzyl carbamate (Moz), p - nitrobenzyl carbamate, p - bromobenzyl Carbamate, p -chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinyl benzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylsulfonylethylcarbamate, 2- ( p -toluenesulfonyl) ethylcarbamate, [2- (1,3-dithianyl)] methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonoisopropylcarbamate M -chloro- p -acyloxybenzylcarbamate, p- (dihydroxyboryl) benzylcarbamate, 5-benzisoxazolylmethylcarbamate, M -nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o -nitrobenzylcarbamate, 3,4-dimethoxybenzylcarbamate, 3- ( O -nitrophenyl) methyl carbamate, t -amyl carbamate, S -benzylthiocarbamate, p- cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexylcarbamate, formate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p - decyl oxy benzylcarbamoyl methoxy Agent, 2,2-dimethoxy-carbonyl-vinyl carbamate, o - (N, N - dimethyl carboxamido) carbamate, 1,1-dimethyl -3- (N, N - dimethyl carboxamido) (2-pyridyl) methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, formate, iso-nicotinyl-carbamate, p - (p'- methoxy-phenylazo) benzyl carbamate, 1-methyl-cyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate Methyl-1- ( p -phenylazophenyl) ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1- Methyl-1- (4-pyridyl) ethyl carbamate, phenyl carbamate, p- (phenylazo) benzylcarbamate, 2,4,6-tri- t- butylphenylcarbamate, 4- (trimethylammonium) Benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

Examples of amino protecting groups such as sulfonamide groups (e.g., -S (= O) ₂ R ^aa ) include, but are not limited to, p -toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl- -Methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methyl (SMS), < RTI ID = 0.0 > 9- < / RTI > Anthracene sulfonamide, 4- (4 ', 8'-dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other amino protecting groups include, but are not limited to, phenothiazinyl- (10) -carbonyl derivatives, N'-p -toluenesulfonylaminocarbonyl derivatives, N' -phenylaminothiocarbonyl derivatives, N- carbonyl derivatives, N - acetyl methionine derivatives, 4,5-diphenyl-3-oxazoline-2-one, N - phthalimide, N - di-thiazol succinimide (Dts), N -2,3- diphenyl Maleimide, N -2,5-dimethylpyrrole, N- 1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl- -Triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5- N -methylamine, N -allylamine, N - [2- (trimethylsilyl) ethoxy] methylamine (SEM), N- 3- acetoxypropylamine, N- 3-pyrrolin-3-yl) amine, a quaternary ammonium salt, N -benzylamine, N -di (4-methoxyphenyl) methylamine, N- N-triphenylmethyl amine (Tr), N - [( 4- methoxyphenyl) diphenylmethyl] amine (MMTr), N-phenyl -9- fluorenyl amine (PhF), N -2,7- dichloro- 9-fluorenyl-methylene amine, N - ferrocenyl methylamino (Fcm), N -2- amino-picolyl N '- oxide, N -1,1- dimethyl-thio-methylene amine, N - benzylidene amine, Np - methoxy ethoxy-benzylidene amine, N - methylene diphenyl amine, N - [(2- pyridyl) mesityl] methylene amine, N - (N ', N'- dimethylaminomethylene) amine, N, N'- isopropylidene diamine, Np - knit Robben tired den amine, N - raise silica den amine, 5- chloro-N- raised silica den amine, N - (5- chloro-2-hydroxyphenyl) phenylmethylene amine, N - cyclohexylidene Amine, N - (5,5-dimethyl-3-oxo-1-cyclohexenyl) amine, N -borane derivative, N -diphenylboronic acid derivative, N - [phenyl (pentacarbonylchromium- or tungsten) N -benzylamine, N -copper chelate, N -zinc chelate, N -nitroamine, N -nitrosamine, amine But are not limited to, N- oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzylphosphoramidate, Amidate, benzenesulfenamide, o -nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide And 3-nitropyridine sulfene amide (Npys).

In certain embodiments, the substituent present on the oxygen atom is an "oxygen protecting group." Oxygen protecting group, Non-limiting examples ^{-R aa, -N (R bb)} 2, -C (= O) R aa, -C (= O) OR aa, -C (= O) SR aa, -C ( ^{= O) N (R bb)} 2, -C (= NR bb) R aa, -C (= NR bb) OR aa, -C (= NR bb) N (R bb) 2, -S (= O) _{^{R aa, -SO 2 R aa,}} -Si (R aa) 3, -P (R cc) 2, -P (R cc) 3, -P (= O) 2 R aa, -P (= O) ( _{^{R aa) 2, -P (=}} O) (OR cc) 2, -P (= O) 2 N (R bb) 2, and -P (= O) (including a NR ^bb) _2, where R ^aa , R ^bb , and R ^cc are defined as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting groups in Organic Synthesis , TW Greene and PGM Wuts, 3 ^rd edition, John Wiley & Sons, 1999, Are included herein.

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), t -butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), benzyloxymethyl ), p -methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy) methyl ( p- AOM), guaiacol methyl (GUM), t -butoxymethyl, ), Siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl ), Tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydro 4-methoxypiperidin-4-yl (CTMP), 1 - [(2-chloro-4-methylphenyl) 4-dioxan-2-yl, tetrahydrofuranyl, tetra Dithiothiopyranyl, 2,3,3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1- Methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2- , 2-trichloro ethyl, 2-trimethylsilyl-ethyl, 2- (phenyl selenide carbonyl) ethyl, t - butyl, allyl, p - chlorophenyl, p - methoxyphenyl, 2,4-dinitrophenyl, benzyl, p -methoxybenzyl, 3,4-dimethoxybenzyl, o- nitrobenzyl, p-nitrobenzyl, p-halo-benzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenyl benzyl, 2-picolyl Picolyl, 3-methyl-2-picolyl N -oxide, diphenylmethyl, p, p'- dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl , p- methoxyphenyldiphenylmethyl, di ( p -methoxyphenyl) phenylmethyl, tri ( p -methoxyphenyl) methyl, 4- (4'-bromophenacyloxyphenyl) diphenylmethyl, ', 4 "-tris (4,5-dichlorophthalate (Imidophenyl) methyl, 4,4 ', 4 "-tris (regolyloxyphenyl) methyl, 4,4' ) Bis (4 ', 4 "-dimethoxyphenyl) methyl, 1,1-bis (4-methoxyphenyl) -1'-pyrenylmethyl, , Benzisothiazolyl S, S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triethylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl, t -butyldimethylsilyl (TBDMS), t -butyldiphenylsilyl silyl, tri - p - silyl (xylyl) silyl, triphenyl silyl, diphenylmethyl silyl (DPMS), t - butyl-methoxy-phenyl silyl (TBMPS), formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, Trichloroacetate, trifluoroacetate, methoxyacetate, Methoxy-phenyl acetate, phenoxy acetate, p - chlorophenoxy acetate, 3-phenyl-propionate, 4-oxo-pentanoate (Le disadvantage carbonate), 4,4- (ethylene- dithio) pentanoate (Le disadvantage Benzoate, p -phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), and the like. , Methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- (trimethylsilyl) ethyl carbonate (TMSEC) ), Ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, p -nitrophenyl carbonate, benzyl carbonate, p -methoxybenzyl carbonate, 4-dimethoxy-benzyl carbonate, o - nitrobenzyl Carbonate, p - nitrobenzyl carbonate, S - benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodo-benzoate, 4-O map butyrate, 4-nitro-4 methyl-pentanoate, o - (di-bromomethyl) benzoate, 2-formyl-sulfonate, 2- (omega T) ethyl, 4- (omega-methylthiophene-ethoxy) butyrate, 2- (omega-methylthiophene Dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,6-dichloro-4-methylphenoxyacetate, 2,6- 1, 1-dimethylpropyl) phenoxy acetate, chloro-di-phenyl acetate, isobutyrate, monomethyl succinate, (E) -2-methyl-2-pentenoate unit, o - (methoxycarbonyl) benzoate, α- naphthoate, N, N, N ', N' - tetramethyl-phosphorothioate dia mi date, N - phenyl carbamate, dimethyl phosphino tea oil, 2,4-dinitrophenyl seolpe carbonate, sulfate, methane Sulfonate (mesylate), benzyl sulfonate, and tosylate (Ts). In order to protect the 1,2- or 1,3-diol, the protecting group may be selected from the group consisting of methylene acetal, ethylidene acetal, 1- t -butyl ethylidene ketal, 1-phenylethylidene ketal, (4- methoxyphenyl) ethyl Cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p -methoxybenzylidene acetal, 2-cyclohexylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal, , 4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidenacetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene orthoester, 1-methoxyethylidene ( N, N -dimethylamino) ethylidene derivatives such as ortho ester, 1-ethoxyethylidene orthoester, 1,2-dimethoxyethylidene orthoester,? -Methoxybenzylidene orthoester, , α- (N, N'- dimethylamino) benzylidene derivative, 2-oxa-cyclopentenyl butylidene O Sat ester, di-t-butyl silylene group (DTBS), 1,3- (1,1,3,3- tetraisopropyl di siloxanyl alkylpiperidinyl) derivative (TIPDS), tetra-t-butoxy CD siloxane - 1,3-diallyldene derivatives (TBDS), cyclic carbonates, cyclic boronates, ethyl boronates and phenyl boronates.

In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). The sulfur-protecting groups include, but are not limited to, ^{-R aa, -N (R bb)} 2, -C (= O) SR aa, -C (= O) R aa, -CO 2 R aa, -C (= O) N (R bb) 2, - ^{C (= NR bb) R aa} , -C (= NR bb) OR aa, -C (= NR bb) N (R bb) 2, -S (= O) R aa, -SO 2 R aa, -Si _{^{(R aa) 3, -P (}} R cc) 2, -P (R cc) 3, -P (= O) 2 R aa, -P (= O) (R aa) 2, -P (= O) _{^{(OR cc) 2, -P (}} = O) 2 N (R bb) 2, and ^{-P (= O) (NR bb} ) 2 comprises a, in which R ^aa, R ^bb, and R ^cc is as defined herein Lt; / RTI > The sulfur protecting groups are well known in the art and include those described in detail in Protecting groups in Organic Synthesis , TW Greene and PGM Wuts, 3 ^rd edition, John Wiley & Sons, 1999, .

These and other exemplary substituents are described in more detail in the detailed description, examples and claims. The present invention is not limited in any way to the list of examples of such substituents.

As used herein, the terms "salt "," acceptable ", or "pharmaceutically acceptable salt ", when used in contact with, without undue toxicity, irritation, Refers to salts which are appropriate and which correspond to a reasonable effect / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. In J. Pharmaceutical Sciences (1977) 66: 1-19 describe pharmaceutically acceptable salts in detail. Pharmaceutically acceptable salts for the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and hyperchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, Or by using other methods used in the art, such as ion exchange, and the like. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane Propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodic acid, Lactate, lauryl sulfate, maleate, maliate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate Phthalates, p-amides, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, Catechol, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts and the like. Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium, quaternary ammonium, and counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates ≪ / RTI >

As used herein, the term "prodrug" refers to a compound that can be hydrolyzed, oxidized or reacted under biological conditions (e.g., in vitro or in vivo enzyme conditions) to become a pharmacologically active compound. In certain instances, prodrugs have improved physical and / or delivery properties over the parent compound. Prodrugs are typically designed to enhance properties based on the pharmacological, pharmaceutical and / or pharmacokinetic aspects of the parent compound. The advantages of prodrugs may be in their physical properties, such as aqueous enhancement for parenteral administration at physiological pH, as compared to the parent compound, which may enhance absorption in the digestive tract or enhance drug stability in long-term storage .

Other definitions

"Disease," " disorder, "and " condition" are used interchangeably herein.

The term " individual "or" subject "to which administration is contemplated herein includes, but is not limited to, a human or male of all ages, such as a pediatric subject (e.g., Such as cows, pigs, horses, sheep, goats, dogs and / or cats), other primates (eg, mature or elderly)), other primates In some aspects and / or embodiments of the invention, the mammal is a human.

 Herein, "topical administration" or "topical administration" or "local effect" means that the active ingredient or its active metabolite is administered directly to a part, tissue or lesion of the body designed to exert its action ≪ / RTI > adjuvant administration / administration. This may include, for example, topical administration to a portion of the skin or direct injection into a tissue or lesion in need of treatment.

As used herein, unless otherwise stated, a "therapeutically effective amount", "sufficient amount" or "sufficient amount" of a compound refers to the amount of a compound or compound of the present invention that is effective to treat a disease, disorder or condition, without causing significant negative or deleterious side- Amount, or concentration of a compound required to treat or reduce or decrease a particular parameter (e.g., body fat) in a subject's body. The term "therapeutically effective amount" may encompass an amount that improves overall treatment, reduces or avoids the symptoms or factors of the disease or condition, or enhances the therapeutic effect of another therapeutically active agent.

As used herein, the terms "reduce," "reduce," "reduce," "lower," or "reduce" refer to the volume, size, weight, bulk, density , Reducing the amount and / or yield.

As used herein, the term "ablating" means completely eliminating any unwanted or inappropriate bulk, size, weight, bulk, density, quantity and / or quantity of a substance (e.g., excess body fat, do.

As used herein, "sick "," sick "or" sick "refers to an individual diagnosed with a particular disease or condition. As used herein, "likely to be sick" means a person who has not been diagnosed with a particular disease or condition by a medical practitioner, but has a scoring (e.g., genetic and / or physiological scoring) , Refers to an entity.

The terms "treating "," treating ", and "treating ", as used herein, unless otherwise indicated, include the reduction of the severity of a disease or condition, which occurs during the course of a disease or condition, Or delaying or slowing the progress of the process.

As used herein, unless otherwise stated, the terms "prevent," " prevent, "and" prevention "refer to an act of inhibiting or reducing the severity of a disease or condition, before the individual begins to have the specified disease or condition.

Fig. 1 shows a tissue section of treated skin and subcutaneous fat in each of group 1, group 2 and group 3. Compared to vehicle (Group 1), tufloprost (Group 3) involved a decrease in fat cell thickness and fat cell size. Bimatoprost (Group 2) did not show this effect.

In the past, it has been known that amide bimetallic can be used to lower body fat through local or local administration. For example, U.S. Patent Nos. 7,66,912; U.S. Application Publication No. 2010-0234466; Aihara et al., Jpn J Ophthalmol 2011; 55: 600-604; Aydin et al., Cutan Ocul Toxicol (2010) 29: 212-216; Filippopoulos et al., Ophtal Plast Reconstr Surg (2008) 24: 302-307; Nakakura et al., Optom Vis Sci (2011) 88: 1140-1144; Park et al., Jpn J. Ophthalmol (2011) 55: 22-27; Peplinski et al., Optom Vis Sci (2004) 81: 574-577; Tappeiner et al. Klin Monbl Augenheilkd (2008) 225: 443-445; Yam et al., J Ocul Pharmacol Ther (2009) 25: 471-472. Recently, Choi et al. Described the in vitro activity of bimatoprost, fluofrost, and related compounds to inhibit the differentiation of human adipose precursor cells in primary cell cultures. Choi et al., J Ocular Pharm Ther. (2012) 28: 146-152. In the adipocyte differentiation assay, bimatoprost reduced the differentiation to 30% of the control group and the fluofrost decreased to 40% of the control group, but there was no statistical difference. Likewise, bimatoprost has been shown to be slightly less potent against the expression of the adipocyte genes peroxisome proliferator-activated receptor-gamma (PPARg), CCAAT-enhancer-binding protein alpha (C / EBPa) and lipoprotein lipase Showed strong inhibition; There was no statistical difference. In conclusion, the literature teaches bimatoprost as a preferred compound for topical administration to reduce body fat. The publications also suggest that, even though tafloprost has this activity, it is at most equivalent to bimatoprost.

However, it has been found that tafloprost is more effective than topical bimatoprost for body fat reduction. As described herein, topical administration can be applied to a specific onset area of the individual's body, for example, to the breast of a male with a posterior neck fat pad or a female breast mold in a patient with HIV lipodystrophy or Cushing's syndrome ≪ / RTI > Without wishing to be bound by theory, it is believed that the fat reduction due to the administration of the compounds described herein can be reduced by a reduction in the number of adipocytes, a decrease in the volume of one or more adipocytes, a decrease in the maturation of one or more adipocytes, and / And may include dedifferentiation. These effects may be mediated through a prostaglandin or a progaglandin-like receptor, and the compounds according to the present invention may exert their effects as described herein by acting as agonists on these receptors.

Thus, in one aspect, there is provided a compound of formula ( I ) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched Lt; RTI ID = 0.0 > of: < / RTI >

In the above, X is as follows:

-OR ₁ wherein R ₁ is selected from the group consisting of hydrogen, a hydroxy protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, Optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heteroaryl;

-SR ₂ wherein R ₂ is selected from the group consisting of hydrogen, a thiol protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, Aryl, optionally substituted heteroaryl; or

-NR ₃ R ₄ wherein R ₃ and R ₄ are independently selected from the group consisting of hydrogen, an amino protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, Substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or R ₃ and R ₄ are connected to form an optionally substituted heterocyclyl ring.

In another aspect, the step of topically administering to a subject a compound of formula ( I ), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof, And a method of reducing fat in an individual in need thereof.

A compound of formula (I) is other flu Frost (i.e., formula (II), wherein R ₁ is -CH (CH _{3) 2} Im), other flu frost free acid (i.e., formula (II), wherein R ₁ is Im H), the other a group of formula (II) other flu including other flu Frost Frost alkyl esters of formula (III) other flu Frost thioester and formula (IV) in the. The compounds of formula ( I ) are members of the prostaglandin FP receptor agonist class. For example, Nakajima et al, Biol Pharm Bull (2003) 26: 1691-1695; Ota et al, Br J Ophthalmol (2007) 91: 673-676. These drugs have traditionally been used in the eye to lower intraocular pressure to treat glaucoma.

In certain embodiments, a compound of formula ( II ), wherein X is -OR ₁ , or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof Lt; / RTI >

In certain embodiments, compounds of formula ( III ) wherein X is -SR ₂ or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof to provide:

In certain embodiments, a compound of formula ( IV ), wherein X is -NR ₃ R ₄ , or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, Provide prodrugs:

In certain embodiments, R < ₁ > is hydrogen.

In certain embodiments, R < _{1 >} is an oxygen protecting group.

In certain embodiments, R < _{1 >} is an optionally substituted alkyl. In certain embodiments, R ₁ is unsubstituted C ₁ -C ₁₂ alkyl. In certain embodiments, R ₁ is unsubstituted C ₁ -C ₆ alkyl. In certain embodiments, R ₁ is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl, or sec-butyl. In certain embodiments, R ₁ is isopropyl (-CH (CH ₃ ) ₂ ).

In certain embodiments, R < _{1 >} is an optionally substituted alkenyl.

In certain embodiments, R < _{1 >} is an optionally substituted alkynyl.

In certain embodiments, R < _{1 >} is an optionally substituted carbocyclyl.

In certain embodiments, R < _{1 >} is an optionally substituted heterocyclyl.

In certain embodiments, R < _{1 >} is an optionally substituted aryl.

In certain embodiments, R < _{1 >} is an optionally substituted heteroaryl.

In certain embodiments, the compound of formula ( II ) wherein R ₁ is hydrogen is a compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof, It is also referred to herein as tafloprost free acid:

In certain embodiments, the compound of formula ( II ) wherein R < _{1 >} is isopropyl is the following compound or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer or isotopically enriched derivative thereof , Also referred to herein as < RTI ID = 0.0 >

In certain embodiments, R < ₂ > is hydrogen.

In certain embodiments, R ₂ is a thiol protecting group.

In certain embodiments, R < _{2 >} is an optionally substituted alkyl. In certain embodiments, R ₂ is unsubstituted C ₁ -C ₁₂ alkyl. In certain embodiments, R ₂ is unsubstituted C ₁ -C ₆ alkyl. In certain embodiments, R ₂ is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl, or sec-butyl. In certain embodiments, R ₂ is isopropyl (-CH (CH ₃ ) ₂ ).

In certain embodiments, R ₂ is an optionally substituted alkenyl.

In certain embodiments, R < ₂ > is an optionally substituted alkynyl.

In certain embodiments, R ₂ is an optionally substituted carbocyclyl.

In certain embodiments, R ₂ is an optionally substituted heterocyclyl.

In certain embodiments, R < _{2 >} is an optionally substituted aryl.

In certain embodiments, R ₂ is an optionally substituted heteroaryl.

In certain embodiments, R < ₃ > is hydrogen.

In certain embodiments, R < ₃ > is an amino protecting group.

In certain embodiments, R < ₃ > is an optionally substituted alkyl. In certain embodiments, R ₃ is unsubstituted C ₁ -C ₁₂ alkyl. In certain embodiments, R ₃ is unsubstituted C ₁ -C ₆ alkyl. In certain embodiments, R ₃ is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In certain embodiments, R ₃ is isopropyl (-CH (CH ₃ ) ₂ ).

In certain embodiments, R < ₃ > is an optionally substituted alkenyl.

In certain embodiments, R < ₃ > is an optionally substituted alkynyl.

In certain embodiments, R < ₃ > is an optionally substituted carbocyclyl.

In certain embodiments, R < ₃ > is an optionally substituted heterocyclyl.

In certain embodiments, R < ₃ > is an optionally substituted aryl.

In certain embodiments, R < ₃ > is an optionally substituted heteroaryl.

In certain embodiments, R < ₄ > is hydrogen.

In certain embodiments, R < ₄ > is an amino protecting group.

In certain embodiments, R < ₄ > is an optionally substituted alkyl. In certain embodiments, R ₄ is unsubstituted C ₁ -C ₁₂ alkyl. In certain embodiments, R ₄ is unsubstituted C ₁ -C ₆ alkyl. In certain embodiments, R ₃ is methyl, ethyl, isopropyl, n-propyl, n-butyl, tert-butyl, isobutyl or sec-butyl. In certain embodiments, R ₃ is isopropyl (-CH (CH ₃ ) ₂ ).

In certain embodiments, R < ₄ > is an optionally substituted alkenyl.

In certain embodiments, R < ₄ > is an optionally substituted alkynyl.

In certain embodiments, R < ₄ > is an optionally substituted carbocyclyl.

In certain embodiments, R < ₄ > is an optionally substituted heterocyclyl.

In certain embodiments, R < ₄ > is an optionally substituted aryl.

In certain embodiments, R < ₄ > is an optionally substituted heteroaryl.

In certain embodiments, R ₃ and R ₄ are connected to form an optionally substituted heterocyclyl ring.

In another aspect, for reducing or eliminating body fat altogether in an individual, such as a human, the compound of formula ( V ) may be administered, for example, alone or in combination with a compound of formula ( I ) or a pharmaceutically acceptable salt, hydrate, solvate , Stereoisomers, polymorphs, tautomers, isotopically enriched derivatives, or prodrugs thereof:

In the equation,

X is < / RTI >

-OR ₁ wherein R ₁ is selected from the group consisting of hydrogen, a hydroxy protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, Optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heteroaryl;

-SR ₂ wherein R ₂ is selected from the group consisting of hydrogen, a thiol protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, an optionally substituted heterocyclyl, Aryl, optionally substituted heteroaryl; or

-NR ₃ R ₄ wherein R ₃ and R ₄ are independently selected from the group consisting of hydrogen, an amino protecting group, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted carbocyclyl, , Optionally substituted aryl, optionally substituted heteroaryl, or R ₃ and R ₄ are connected to form an optionally substituted heterocyclyl ring;

Z is = 0 or 2 hydrogen atoms;

One of R ₅ and R ₆ is ═O, -OH, or -O (CO) R ₈ group and the other is -OH or -O (CO) R ₈ or R ₅ is ═O and R ₆ Is H, where R ₈ is a saturated or unsaturated acyclic hydrocarbon of about 1-20 carbon atoms or - (CH ₂ ) _m R ₉ where m is 0-10, R ₉ is cycloalkyl of 3-7 carbon atoms, Aryl of 6-10, or heteroaryl of 4-10 carbons having 1-4 heteroatoms selected from the group consisting of N, O and S;

R ₇ is hydrogen, halogen, -OH or -O (CO) R ₁₀ , wherein R ₁₀ is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms, or - ( CH ₂ ) _m R ₁₁ , and R ₁₁ is cycloalkyl having 3 to 7 carbon atoms, aryl having 6 to 10 carbon atoms, or heteroatom having 4 to 10 carbon atoms selected from the group consisting of N, O and S Heteroaryl;

R _{7 '} is hydrogen or halogen;

Y is selected from the group consisting of alkyl, halo, nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy and halo substituted alkyl wherein the alkyl radical comprises 1 to 6 carbon atoms;

y is 0 or 1, x is 0 or 1, with the proviso that both x and y are not 1; And

n is 0 or an integer of 1-3.

In certain embodiments, at least one of R ₇ and R _{7 '} is not hydrogen. In certain embodiments, R ₇ and R _{7 '} are both halogen. In certain embodiments, R ₇ and R _{7 '} are both fluorine. In certain embodiments, at least one of R ₇ and R _{7 '} is halogen. In certain embodiments, at least one of R ₇ and R _{7 '} is fluorine.

Without wishing to be bound by any particular theory, it is understood that one or more of the above compounds may exist as a prodrug. That is, it is not intended to be bound by theory, and the present invention may be, for example, a free acid such as tafloprost free acid, a basic species that is pharmacologically active for the purposes of the present invention, , Amide) can also be a prodrug, i.e. the substrate of a hydrolase (e. G., Esterase, amidase) in the body, resulting in the formation of the corresponding free acid. Because the hydrolytic enzymes may (or may not) be present at various levels in the various parts of the animal's body, they may be selected from the various analogs described herein, depending on the desired route of administration and the location, Opportunity exists. Based on these considered properties, the opportunity to increase the therapeutic index by defining, among various analogs, certain analogues where a low activity prodrug is metabolized more efficiently by the active metabolite within the site, tissue, or cell type to be treated It is also understood to be present. It is understood that the compounds described herein can be prepared with specific compounds that are substrates of esters or amidases, substituted with esters and amides, respectively.

Pharmaceutical compositions and formulations

In certain embodiments, the invention provides a pharmaceutical composition comprising one or more compounds of formula ( I ), ( II ), ( III ), ( IV ) and / or ( V ), or a pharmaceutically acceptable salt, hydrate, solvate, Any of the herein described, including isomers, polymorphs, tautomers, isotopically enriched derivatives or prodrugs ("active ingredient (s)") and optionally one or more pharmaceutically acceptable excipients, A pharmaceutical composition and a formulation for use in the method. In certain embodiments, the composition is suitable for topical, subcutaneous, intradermal, or intralesional delivery.

Pharmaceutically acceptable excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, lubricants and the like, which are suitable for the particular dosage form desired do. General considerations in formulations and / or formulations of pharmaceutical compositions include, for example, Remington's Pharmaceutical Sciences , Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy , 21 ^st Edition (Lippincott Williams & Wilkins, 2005).

The pharmaceutical compositions described herein may be prepared according to any method known in the art of pharmacy. In general, such a method of preparation may comprise the steps of combining the active ingredient with a carrier and / or one or more other auxiliary ingredients, and thereafter formulating the product into a desired single or multi-dose unit and / or, if necessary and / And packaging.

The pharmaceutical composition may be manufactured, packaged and / or sold as a bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, "unit dose" is the individual content of a pharmaceutical composition comprising the active ingredient in the predetermined amount. The amount of active ingredient is generally a reasonable part of the dosage, such as the dosage of the active ingredient to be administered to the subject, and / or such as, for example, one-half or one-third of the dose.

The relative amount of active ingredient, pharmaceutically acceptable carrier and / or optional additional ingredients in the pharmaceutical compositions of the present invention will vary depending upon the identity, body size and / or condition of the subject being treated, as well as the route by which the composition is to be administered will be. For example, the composition may comprise from 0.001% to 100% (w / w) or (w / v) of the active ingredient. In certain embodiments, the composition comprises the active ingredient in a non-limiting example, from about 0.01% to about 90%, from about 0.01% to about 80%, from about 0.01% to about 70%, from about 0.01% to about 60% From about 0.01% to about 10%, from about 0.01% to about 5%, from about 0.01% to about 50%, from about 0.01% to about 40% (W / v) or (w / v) of from about 0.01% to about 2%, from about 0.01% to about 1%, or from about 0.01% to about 0.05% do. In certain embodiments, the composition comprises the active ingredient in an amount of from about 0.001% to about 90%, from about 0.001% to about 80%, from about 0.001% to about 70%, from about 0.001% to about 60% About 0.001% to about 30%, about 0.001% to about 30%, about 0.001% to about 20%, about 0.001% to about 10%, about 0.001% to about 5% (W / v) or (w / v) of from about 0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% to about 1%, or from about 0.001% do. In certain embodiments, the composition comprises the active ingredient in a non-limiting example, from about 0.01% to about 10% (w / w) or (w / v). In certain embodiments, the composition comprises the active ingredient in a non-limiting example, from about 0.01% to about 1% (w / w) or (w / v). In certain embodiments, the composition comprises the active ingredient in a non-limiting example, from about 0.001% to about 10% (w / w) or (w / v). In certain embodiments, the composition comprises the active ingredient in a non-limiting example, from about 0.001% to about 1% (w / w) or (w / v).

Pharmaceutically acceptable excipients used in the preparation of the provided pharmaceutical compositions are inert diluents, dispersing agents and / or granulating agents, surfactants and / or emulsifiers, disintegrating agents, binders, preservatives, buffering agents, lubricants and / or oils . Cocoa butter and suppository waxes, colorants, coatings, sweeteners, flavoring agents and flavoring agents may also be present in the composition.

Examples of diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, , Corn starch, powdered sugar, and the like, and combinations thereof.

Examples of the granulating agent and / or dispersing agent include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, grape gum, citrus pulp, agar, bentonite, cellulose and wood products, (Crospovidone), sodium carboxymethyl starch (sodium starch glycollate), carboxymethyl cellulose, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, Methylcellulose (croscarmellose), methylcellulose, pregellatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, 4 A quaternary ammonium compound and the like, and combinations thereof.

Examples of surfactants and / or emulsifiers include lipid / natural emulsifiers such as acacia, agar, alginic acid, sodium alginate, tragacanth, chondroitin, xanthan, pectin, gelatin, yolk, casein, wool, cholesterol, wax Long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triethanolamine, and the like) (E.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan (such as carboxymethylcellulose, polyvinylpyrrolidone, , Cellulosic derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxy Polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan fatty acid esters Examples of the surfactant include ethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan mono Polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol < (R) > ), Sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether Ether (Brij 30), poly (vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate , Pluronic F 68, Poloxamer 188, settimorium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, Lipoderm ^® , and the like, and / or combinations thereof. In certain embodiments, the excipient is Lipoderm ^® .

Examples of binders include starch (e.g., corn starch and starch paste), gelatin, sugar (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, Gum arabic, acacia, sodium alginate, extract of irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, Cellulose acetate, poly (vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan (Larch arabogalactan), which are known to those skilled in the art, such as ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, ), Alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salt, silicic acid, polymethacrylate, wax, water, alcohol, etc. and / .

Examples of preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acid preservatives, and other preservatives.

Examples of antioxidants include but are not limited to alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, Sodium bisulfite, sodium metabisulfite, and sodium sulfite.

Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, tri edetate, calcium disodium edetate, ditassium edetate, etc.) Salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Examples of antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chlorocresol, cresol, ethyl alcohol, glycerin , Hexetidine, imidourea, phenol, phenoxyethanol, phenylethyl alcohol, phenyl mercurin nitrate, propylene glycol, and thimerosal.

Examples of antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

Examples of the alcohol preservative include ethanol, polyethylene glycol, phenol, phenol compounds, bisphenol, chlorobutanol, hydroxybenzoate and phenylethyl alcohol.

Examples of acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

Other preservatives include but are not limited to tocopherol, tocopherol acetate, dertoroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium laurylsulfate Sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, phenonib, methyl paraben, Germall 115, Germaben II, Neolone, Kathon and Euxyl. In certain embodiments, the preservative is an antioxidant. In another embodiment, the preservative is a chelating agent.

Examples of buffering agents include, but are not limited to, citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium gluconate, calcium gluconate, Calcium phosphate, calcium acetate, potassium chloride, potassium gluconate, potassium gluconate, calcium lactate, propanoic acid, calcium regrinate, pentanoic acid, basic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxy phosphate, Sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, sodium metabisulfite, sodium basic phosphate, monobasic sodium phosphate, monobasic potassium phosphate, potassium phosphate mixture, potassium phosphate mixture, sodium acetate, , Comprises a sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water is the lack of water, isotonic saline, Ringer's solution, ethyl alcohol, and the like, and combinations thereof.

Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate , Sodium lauryl sulfate, and the like, and combinations thereof.

Examples of oils are almonds, apricot kernel, avocados, babassu, bergakot, black current seed, borage, cade, chamomile, canola, caraway, Eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, cucumber butter, coconut, cod liver, coffee, corn, cottonseed, emu ), Isopropyl myristate, jojoba, kukui nut, lavendin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango, meadow Peach kernel, peanut seeds, pumpkin seeds, rapeseed, rapeseed, peach kernel, peach kernel, peanut seeds, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, Rice bran, rosemary, safflower, sandalwood, sasquana, savory, mountain Include wood (sea buckthorn), sesame, shea butter (shea butter), silicone, soybean, sunflower, tea tree, thistle (thistle), camellia (tsubaki), vetiver (vetiver), walnut and witjeom (wheat germ) oils. The oil may be selected from, but is not limited to, butyl stearate, capryl triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, Alcohols, silicone oils, and combinations thereof.

Liquid dosage forms for mucosal and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. This liquid dosage form may contain, in addition to the active ingredient, water or other solvents such as ethyl carbonate, ethyl acetate, benzyl benzoate, dimethyl formamide, fatty acid esters of sorbitan, polysorbates, solubilizing agents such as alcohols (E.g., ethyl alcohol, isopropyl alcohol, tetrahydrofurfuryl alcohol, benzyl alcohol, glycerol and glycols such as 1,3-butylene glycol, propylene glycol, polyethylene glycol) Such as corn oil, germ oil, olive oil, castor oil, and sesame oil, cremophor, cyclodextrin, polymers), and mixtures thereof, which are commonly used in the art . In addition to the inert diluent, the composition for mucosal administration may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and flavoring agents. In certain embodiments, for parenteral administration, the active ingredient is mixed with a solubilizing agent such as a cremophor, an alcohol, an olive, a modified oil, a glycol, a polysorbate, a cyclodextrin, a polymer, and combinations thereof.

The injectable formulations, such as sterile injectable aqueous or oily suspensions, may be formulated according to the known art using suitable dispersing or suspending agents and suspending agents. The sterile injectable preparation may be a solution in a sterile injectable solution, suspension or emulsion, for example in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be employed include water, Ringer's solution U.S.P. And isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blending oil, such as synthetic mono- or diglycerides, may be used. In addition, fatty acids such as oleic acid are used in feed preparations.

The injectable formulations may be sterilized, for example, by injection through a sterile filter in the form of a sterile, solid composition which may be dissolved or dispersed prior to use, for example, by filtration through a bacterial retention filter, sterile water or other sterile injectable medium .

Compositions for rectal or vaginal administration typically comprise a suitable non-parenteral excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax that is solid at ambient temperature but liquid at body temperature to dissolve the active ingredient in the rectum or vagina, By mixing it with an active ingredient.

Dosage forms for topical and / or transdermal administration of the active ingredient may include ointments, powders, creams, lotions, gels, powders, solutions, sprays, inhalants and / or patches. In general, the active ingredient may be mixed with the pharmaceutically acceptable carrier under sterile conditions, and / or any necessary preservatives and / or buffers may be required. Additionally, the present invention encompasses the use of transdermal patches, which are often beneficial to provide the active ingredient in a controlled manner to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispersing in the appropriate medium of the active ingredient. Alternatively or additionally, the rate can be controlled by providing a rate controlling membrane, and / or by dispersing the active ingredient in the polymer matrix and / or gel.

Suitable devices for use in delivering the pharmaceutical compositions within the dermis described herein include those described in U.S. Patent 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; And short needle mechanisms such as those described in 5,417,662. The dermal composition may be administered by a device that limits the length of the needle effective to penetrate the skin, such as the device described in PCT Publication No. WO 99/34850 or its functional equivalents. A jet injection device is suitable for delivering the liquid vaccine to the dermis through a liquid jet injector and / or through a needle which forms the jet through the stratum corneum and reaches the dermis. The jet injection device is described, for example, in U.S. Patent Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; And PCT Publication Nos. WO 97/37705 and WO 97/13537. A ballistic powder / particle delivery device using a compressed gas to accelerate the powdered vaccine through the skin's outer layer and into the dermis is also suitable. As another example, or additionally, existing syringes can also be used for dermal administration, which is the classical mantoux method.

Formulations suitable for topical administration include, but are not limited to, liquid and / or semi-liquid preparations such as ointments, lotions and oil-in-water and / or water-in-oil emulsions such as creams, ointments and / And / or suspending agents. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) of the active ingredient, but the concentration of the active ingredient may be high enough to limit the solubility of the active ingredient in the solvent. Formulations for topical administration may additionally include one or more of the additional ingredients described herein.

The pharmaceutical composition of the present invention can be manufactured, packaged and / or sold as a formulation suitable for eye administration. Such formulations may be in the form of drops, such as solutions and / or suspensions containing, for example, 0.1 / 1.0% (w / w) of the active ingredient in an aqueous or oily liquid carrier. The eyedrops may further comprise one or more buffering agents, salts and / or other additional ingredients as described herein. Useful eye-ready formulations include formulations comprising the active ingredient in microcrystalline form and / or in the form of a liposome formulation. Points and / or eye drops are therefore considered to be within the scope of the present invention.

Although the description of the pharmaceutical compositions provided herein is basically directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will appreciate that these compositions are generally suitable for administration to all kinds of animals. Variations of pharmaceutical compositions suitable for administration to humans in order to make the composition suitable for administration to a variety of animals are well recognized and veterinary and pharmacologists of the art can design and / or perform such modifications through routine experimentation. General considerations for formulation and / or production of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

The present invention also includes pharmaceutical packs and / or kits. The pharmaceutical packs and / or kits provided may include compositions and containers (eg, vials, ampoules, bottles, syringes and / or dispensing packages or other appropriate containers). In some embodiments, the provided kit may optionally further comprise a second container containing an appropriate aqueous carrier for dilution or suspension of the composition provided in its preparation for administration to the individual. In some embodiments, the contents of the formulation vessel and the solvent vessel provided are combined to produce one or more unit dosage forms.

The active ingredient may be administered using any amount effective for treatment and any topical route of administration. The actual amount required will depend on the individual, such as the age, sex and overall dryness of the individual, the severity of the infection, the specific composition, the mode of administration, the mode of administration, and the like.

The active ingredient is typically formulated in dosage unit form for ease of administration and uniformity of dosage. However, the total daily usage of the compositions of the present invention will be determined by the attending physician within the scope of adequate medical judgment. The specific therapeutically effective dose level for any individual subject will depend on the severity of the symptoms and symptoms being treated; The activity of the specific active ingredient used; The specific composition used; Gestational age, body weight, overall health status, gender and diet; The time of administration, the route of administration and the rate of excretion of the particular active ingredient used; Treatment period; Drugs used in combination or concurrently with the particular active ingredient used; And other factors well known in the medical arts.

The active ingredient may be administered by any suitable local route, parenteral (e.g., subcutaneous, intradermal, intra-focal, e.g., lipoma) and topical administration (e.g., transdermal, intracapsular, ocular). In general, the most suitable route of administration will depend on a variety of factors, including the nature of the active ingredient (eg, stability in the body part being administered), the condition of the individual (eg, whether the individual is tolerable for subcutaneous administration) will be.

The actual amount of active ingredient needed to achieve a therapeutically effective amount will vary depending upon, for example, the species of the individual, the age, the severity of the various general health conditions, side effects or disorders, the identity of the individual compound (s) . Preferred doses are: three times daily, twice daily, once daily, every two days, every three days. Weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, a preferred dosage is delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more administrations) . As described in the appended examples, daily administration to an individual may (but is not necessarily desirable) be suited to achieving the desired effect. The daily dosing schedule is believed to be convenient for human use. The active ingredient may be administered by itself repeatedly, without special equipment or training, but a medical professional may administer the active ingredient to the individual.

In certain embodiments, a therapeutically effective amount of an active ingredient for administration to a 70 kg human adult at least once per day includes from about 0.00001 mg to about 3000 mg, from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 0.0001 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, About 0.00001 mg, about 0.00001 mg, about 0.00001 mg, about 0.01 mg, about 0.00001 mg, about 0.1 mg, about 0.00001 mg, about 0.00001 mg, about 0.00001 mg, , From about 0.001 mg to about 1 mg, from about 0.0001 mg to about 1 mg, or from about 0.0001 mg to about 0.01 mg. A therapeutically effective amount can include, for example and without limitation, from about 0.001 to about 10.0% (w / v), or from about 0.01 to about 10.0% (w / v) of the active ingredient in a liquid or semi-solid dosage form. It will be appreciated that dosage ranges as described herein are guides for administration of the pharmaceutical compositions provided to an adult. For example, the amount administered to a child or adolescent may be determined by a medical practitioner or a person skilled in the art, and may be equal to or less than the amount administered to an adult.

In addition, the active ingredient may be administered in combination with one or more additional therapeutically active ingredients ("agent" or "active agent"). The compound or composition may be administered prior to, or after administration with one or more additional agents. In general, the active ingredient (s) and each additional active agent (s) will be administered in a dose and / or time schedule prescribed for the ingredient and formulation. The active and active agents used in this combination may be administered together in a single composition or separately in separate compositions. The specific combination for carrying out the usage will take into account the compatibility of the active ingredient with the active agent and / or the desired therapeutic effect to be achieved. In general, additional active agents used in combination are expected to be used at levels that do not exceed the level at which they are used, respectively. In some embodiments, the level used in combination will be lower than the level used individually.

The active ingredient may be administered in combination with an active agent that improves bioavailability, reduces and / or modifies metabolism, inhibits release, and / or modifies the body's distribution. In addition, the therapeutic agent employed may achieve a desired effect on the same disorder (e. G., The active ingredient may be administered in combination with an anti-inflammatory agent and / or antidepressant, etc.) and / or may achieve other effects Control).

Examples of active agents include, but are not limited to, anticancer agents, antibiotics, anti-obesity agents, antiviral agents, anesthetics, anti-coagulants, steroids, steroidal anti-inflammatory agents, non-scrotalic antiinflammatory agents, antihistamines, Antagonists, antipsychotics, antidepressants, antihistamines, antihistamines, antihistamines, antihistamines, antihistamines, antihistamines, antihistamines, antigens, antigens, antigens, Neuroleptics, neuroleptics, hypnotics, psychostimulants, anti-convulsants / anti-epileptics (eg Neurontin, Lyrica, valproates (eg Depacon), and other tranquilizers), muscle relaxants, Antagonists, anti-cholinesterases, beta-adrenergic blockers, diuretics, cardiovascular agents, vasoactive agents, vasodilators, anti-angiogenic agents, anti- Hypertension, angiogenesis, Modulators of cell-extracellular matrix interactions (eg, cell growth inhibitors and anti-adhesion molecules), or DNA, RNA, protein-protein interactions, inhibitors / intercalators of protein-receptor interactions. The active agent may be a drug compound (e.g., a compound approved by the Food and Drug Administration provided in the Federal Regulations (CFR)), a peptide, a protein, a carbohydrate, a monosaccharide, an oligosaccharide, a polysaccharide, a nuclear protein, a muco protein, a lipoprotein, Small molecules linked to proteins, small molecules such as glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

Body fat reduction method

In certain embodiments, the invention provides a pharmaceutical composition comprising one or more compounds of formula ( I ), ( II ), ( III ), ( IV ) and / or ( V ), or a pharmaceutically acceptable salt, hydrate, solvate, Comprising the step of locally administering an isomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof to a subject in need thereof.

Fat loss may include fat loss due to one or more measurements of volume, size, weight, bulk, density, quantity and / or quantity. The present invention provides a method of reducing fat by more than 75%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, or 5% . For example, fat loss may also include a quantitative decrease in fat cells (e. G., A reduction in the number of fat cells), a decrease in the volume of adipocytes, a decrease in maturation of adipocytes, and / or dedifferentiating of adipocytes.

In certain embodiments, the body fat is localized, such as abdomen, breast, breast, buttocks, hips, thighs, legs, knees, arms, chin, neck and / or face.

In certain embodiments, the subject is selected from the group consisting of obesity, excessive breast fat, excessive jaw fat, gynecomastia, drug induced obesity, hypothyroidism, hypoparathyroidism, hypothalamic obesity, polycystic ovarian disease, depression, Growth Hormone Deficiency, Growth Hormone Deficiency, Leptin Deficiency or Tolerance, Cushing's Syndrome, Caustic Cushing's Syndrome, Posterior Cervical Syndrome, Cerebral Palsy Syndrome, Cerebral Palsy Syndrome, Of patients with acute pancreatitis or acute pancreatitis, such as acromegaly / posterior neck hyperplasia ("buffalo hump"), facial edema, HIV lipodystrophy, orbital fat prolapse, age-related descent of abnormal fat, , Lipidemic or < RTI ID = 0.0 > madelon < / RTI > In certain embodiments, the subject is suffering from or susceptible to obesity, gynecomastia, HIV lipodystrophy, lipoma, or excessive fat symptoms of the jaw.

In certain embodiments, the route of administration is selected from the group consisting of topical, subcutaneous, intradermal, and intraluminal. In certain embodiments, the route of administration is topical. In certain embodiments, the site of administration is selected from the group consisting of skin, eyes, or mucosa. In certain embodiments, the route of administration is selected from the group consisting of subcutaneous, intradermal, and intralesional. In certain embodiments, the administration is in a body part selected from the group consisting of abdomen, chest, breast, buttocks, hips, thighs, legs, knees, arms, jaws, neck and face. In certain embodiments, topical administration is transdermal administration.

In certain embodiments, the subject is an individual having a medicament (e.g., cortisol and analog, corticosteroid, megace, sulphonylurea, antiretroviral, antidepressant, monoamine oxidase inhibitor, selective serotonin reuptake inhibitor, oral contraceptive, Insulin or insulin form, risperidone, clozapine, and thiazolidinedione).

In certain embodiments, the subject has excessive body fat due to changes in hormone status (e.g., as a result of physiological changes such as pregnancy or menopause).

In certain embodiments, the individuals with excessive body fat are those who are quitting, or have recently been quit.

In certain embodiments, the subject has body fat in a cosmetically meaningful manner, for example, due to orbital fat prolapse or agglomeration of fat due to aging.

Aspects of the present invention may be used in various types of surgery, whether used preoperatively, peri-operatively, or post-operatively. The present invention also provides a method of treating a subject suffering from a condition prior to an orthopedic procedure that may improve abdominal, thoracic, tumor, endocrine, neurological, transplant and skin surgery, which may improve surgical exposure, Or subsequent use is also contemplated.

Example

It is to be understood that, throughout the specification, where a composition has, comprises, or includes certain components, or where the method is described as having, containing, or comprising specific procedural steps, the compositions of the present invention are essentially Configured or constructed and that the methods of the present invention are also considered to be essentially composed or constituted by the stated steps of the process. In addition, it should be understood that the order of steps or the order of performing a particular action is not critical so long as the invention remains operative. In addition, two or more steps or actions may be performed simultaneously.

In view of the foregoing description, the specific non-limiting embodiments described below are intended for purposes of illustration only and are not intended to limit the scope of the invention in any way.

Example 1

( db - / db -) mice were randomly selected. Six-week-old mice were randomly assigned to groups potentially and the following treatment guidelines were assigned. (n = 5 rats / group):

Table I. group cure Formulation dosage One Vehicle Not applicable Daily, 0.1 cc on the flanks 2 Bimatofrost 5 mM topical (5 mM, 2.09 mg / ml) Daily, 0.1 cc on the flanks 3 Tapu Frost 5 mM topical (5 mM, 2.27 mg / ml) Daily, 0.1 cc on the flanks

At the start of the experiment, the right lateral fur of each animal was short-cut and depilated. The animals were placed under the same conditions and freely consumed the food. Animals were weighed daily. After 21 days of treatment, the skin and surrounding fat samples were collected from the treated side, fixed in formalin, and stained with hematoxylin and eosin for histological examination.

Table II summarizes the weight change in each group during the 21 day experiment. In animals treated with vehicle and bimatoprost, body weight was increased by about 23-24% in baseline body weight, while animals treated with tafloprost showed weight loss of about 8% in baseline body weight.

Table II. group cure Absolute weight change (g) Relative weight change (% 0 day) One Vehicle 6.9 24.5% 2 Bimatofrost 6.4 22.9% 3 Tapu Frost -2.4 * * -8.2%

* p <.01 by Tukey

Figure 1 shows representative tissue fragments for treated skin and subcutaneous fat in groups 1, 2 and 3, respectively. Compared to vehicle (Group 1), tafloprost (Group 3) was accompanied by a decrease in fat thickness and fat cell size. Bimatoprost (Group 2) did not show this effect.

That is, according to the above experiment, it was confirmed that the topical administration of tafloprost inhibits adipose tissue and adipocytes in mice, and this effect is remarkably superior to that observed when topical administration of bimatoprost with equivalent dose.

Example 2

The following experiments were conducted to determine whether topically administered tufloprost reduces the fat in the posterior neck fat pad of HIV-seropositive patients suffering from HIV lipodystrophy undergoing antiretroviral therapy, Of the study population.

Randomized, double-blind trial of eligible individuals (e. G., N = 40) who were suffering from HIV lipodystrophy and abnormally accumulated fat on the dorsal neck. Individuals were randomly assigned 1: 1 with a group of administrations of troprostos, such as 0.03%, into the appropriate transdermal vehicle and vehicle alone. The vehicle, for example, a ^{Lipoderm ® (PCCA, Houston, Texas} ). Unit-dose syringes (e. G., 0.5 ml / syringe) are provided by research pharmacists to individuals; The syringe is not indicated for the presence of tafloprost or vehicle.

The subject is trained to apply the contents of one syringe once a day to the opposite side of the dorsal neck.

Performs a series of ultrasound (US) and / or computer tomography (CT) scans at the beginning of the experiment and monthly. The treatment is carried out for 6 months.

Over time, such as 3 months after treatment, it is expected that tafluprost will be accompanied by a decrease in the depth and cross-sectional area of the posterior cervical fat compared to the vehicle alone, as confirmed by serial US or CT.

Example 3

The following illustrates the clinical use for topical administration of tafloprost to reduce functional and / or cosmetically significant local fat accumulation.

A 56-year-old woman in the cabin crew is dissatisfied with work-related disturbances and excessive fat accumulation in the hips and thighs, which reduces self-esteem. Her physician recommends diet and exercise. The woman lost 7 pounds, but no noticeable reduction in fat accumulation was observed. The woman contacts the plastic surgeon, but refuses liposuction because of potential side effects.

Plastic surgeons prescribe a daily fluffy frost ointment on their hips and thighs as a treatment for fat deposits. After a period of time, such as a few days to a few months, the fat accumulation in the hips and thighs of this woman is reduced.

Example 4

The following example illustrates the clinical use of topical prophylaxis for the relief of escaped orbital fat.

A 67-year-old man contacts the oculoplastic surgeon and complains about "bag under the eyes." As a result, the orbital fat of both lower eyelids was found to be a menopausal orbital fat prolapse. The eye plastic surgeon prescribes a daily fluffy frost ointment on the lower eyelid. After a period of time, for example, 2 to 26 weeks, the orbital fat accumulation under the eyes is reduced.

Example 5

The following example illustrates a randomized controlled trial of human subjects to test whether fluofurost ointment reduces escaped orbital fat.

Enter a randomized double-blind trial on eligible individuals (eg, n = 20) with orbital fat prolapse in the lower eyelid. Subjects are randomly assigned to 50%: 50% to apply the ophthalmic ointment to the right or left lower eyelid and the placebo ointment is applied to the opposite eye. The subject is instructed to apply a small amount (approximately 0.1 ml) of ointment to the lower eyelid once a day.

A series of clinical, photographic, and magnetic resonance imaging (MRI) scans are performed at regular intervals during the experiment. Treatment lasts 12 weeks.

After a period of time, such as 6-12 weeks, it is anticipated that the fluofurost ointment will involve a more subjective and objective reduction of the orifice fat fill, thickness, and / or volume compared to vehicle alone.

Other Embodiments

All patents, patent applications, and literature references mentioned in the present application are hereby incorporated by reference.

The foregoing describes some non-limiting embodiments of the present invention. It will be understood by those skilled in the art that various changes and modifications may be made therein without departing from the spirit or scope of the invention as defined by the appended claims.

Claims (27)

A therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof; And
&Lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable excipient,
Pharmaceutical compositions for reducing body fat:

Wherein R ₁ is hydrogen or C ₁ -C ₆ alkyl. 2. The pharmaceutical composition according to claim 1, wherein R &lt; _{1 &gt;} is hydrogen. A pharmaceutical composition according to claim 1, wherein R ₁ is C ₁ -C ₄ alkyl. The pharmaceutical composition according to claim 3, wherein the compound is a compound of the formula:

4. The pharmaceutical composition according to claim 3, wherein R &lt; ₁ &gt; is ethyl. 2. The pharmaceutical composition according to claim 1, wherein the composition is suitable for topical, subcutaneous, intradermal or intralesional delivery. 2. The pharmaceutical composition according to claim 1, wherein said composition comprises 0.001% to 1% (w / w) or (w / v) of said compound. 2. The pharmaceutical composition according to claim 1, wherein the composition comprises 0.01% to 1% (w / w) or (w / v) of the compound. 2. The pharmaceutical composition according to claim 1, wherein the body fat is located in the abdomen, chest, breast, buttocks, buttocks, thighs, legs, knees, arms, jaws, neck or face. The pharmaceutical composition according to claim 1, wherein the body fat is orbital fat. 11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the composition is a cream, a gel, an ointment or a lotion. A transdermal patch comprising the composition of claim 1. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete

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